Erythromycin A derivatives

ABSTRACT

An erythromycin A derivative represented by Formula                    
     wherein R 1  is a group represented by the formula:                    
     a group represented by the formula:                    
     (c) pyridylacetyl, (d) cycloalkylmethyl or (e) 1,2 bis-(ethoxycarbonyl)vinyl, R 2  is the same group as defined for R 1 , hydrogen, alkyl, alkanoyl, alkoxycarbonyl, R 1  and R 2  together may form ═CH—R 14 , or R 1  and R 2  together with the nitrogen atom to which they are attached may form:                    
     R 3  is hydrogen, alkyl or cinnamyl, R 4  is hydrogen, acetyl, ethylsuccinyl or nicotinoyl, A is —OC(═O)—R 17 , —OC(═O)—CH 2 —R 17 , —OC(═O)—NH—R 17 , —O—R 17  or —OC(═O)—O—R 17 , and R 5  and R 6  are each hydrogen or alkyl.

TECHNICAL FIELD

The present invention relates to novel derivatives of antibioticerythromycin A.

BACKGROUND ART

Erythromycin A is an antibiotic clinically widely used as an agent fortreating infectious diseases caused by Gram-positive bacteria,mycoplasmas, etc. However, erythromycin A is decomposed by the gastricacid due to instability to acids, and thus have a drawback of noconstancy of movement in the body. Hitherto many erythromycin Aderivatives have been prepared for the purpose of the improvement of thebiological or pharmacological properties. For example, it is reportedthat 6-O-methylerythromycin A derivatives have an improved stability toacids and have a superior in vivo antibacterial activity in comparisonwith erythromycin A when administered orally (U.S. Pat. No. 4,331,803).There are also recent reports relating to 11,12-cyclic carbamatederivatives prepared from 6-O-methylerythromycin A as a startingmaterial with the aim of expansion of antibacterial spectrum as well asa stability to acids (EP. patent No. 487411 and U.S. Pat. No.4,742,049). In addition, the present inventors refer to theantibacterial activity of the ester derivatives at the 3-position (EP.Patent No. 619320).

An object of the present invention is to provide a novel antibioticerythromycin A derivative or a salt thereof having a strongantibacterial activity against not only known erythromycin-sensitivebacteria but also erythromycin-resistant bacteria which recently areshowing a tendency to increase, and a composition comprising the same asan effective component.

Other objects of the present invention are to provide a method for thetreatment of a bacterially infectious disease which comprisesadministering a pharmaceutically effective amount of the above-mentionederythromycin A derivative or a salt thereof to patients, and use of theabove-mentioned erythromycin A derivative or a salt thereof for thetreatment of a bacterially infectious disease.

DISCLOSURE OF THE INVENTION

As a result of various researches on the antibacterial activity oferythromycin A derivatives, the present inventors have found that, among6-O-methylerythromycin A 11,12-cyclic carbamate derivatives, inparticular, the derivatives which are substituted by a substitutedaminoalkyl group on the nitrogen atom forming the cyclic carbamate ringand converted into an ester at the 3-position have a strongantibacterial activity against erythromycin-resistant bacteria, and havefurther studied about analog compounds thereof, whereby the presentinvention has been accomplished.

The present invention relates to an eythromycin A derivative representedby Formula (I):

[wherein n is an integer of from 1 to 4,

R¹ is a group represented by the formula:

(wherein p is 0 or 1, Z is a nitrogen atom or CH; R⁷, R⁸ and R⁹ are eacha hydrogen atom, a halogen atom, an alkyl group having 1 to 5 carbonatoms, a nitro group, an amino group, an acetylamino group, an aminogroup substituted by 1 or 2 alkyl groups having 1 to 3 carbon atoms, ahydroxyl group, a cyano group, an alkyl group having 1 to 3 carbon atomssubstituted by 1 to 3 halogen atoms, an alkoxy group having 1 to 5carbon atoms or a phenyl group, or R⁷ and R⁸ are attached to the carbonatoms which are attached side by side, and together form amethylenedioxy group, or R⁷ and R⁸ are attached to the carbon atomswhich are attached side by side, and together with the carbon atoms towhich they are attached form a benzene ring, R¹⁰ and R¹¹ are each ahydrogen atom, or R¹⁰ and R¹¹ together form an oxo group), a grouprepresented by the formula:

(wherein R¹⁰ and R¹¹ are as defined above, M is an oxygen atom, a sulfuratom, —NCH₃ or —NH, or R¹² and R¹³ are each a hydrogen atom, or R¹² andR¹³ together with the carbon atoms to which they are attached form abenzene ring), a pyridylacetyl group, a cycloalkylmethyl group having 4to 8 carbon atoms or a 1,2-bis(ethoxycarbonyl)vinyl group,

R² is the same group as defined for R¹, a hydrogen atom, an alkyl grouphaving 1 to 5 carbon atoms, an alkanoyl group having 2 to 6 carbon atomsor an alkoxycarbonyl group having 2 to 6 carbon atoms, R¹ and R²together form a group of the formula: ═CH—R¹⁴ (wherein R¹⁴ is a phenylgroup, a phenyl group substituted by nitro group(s), cyano group(s) oralkyl group(s) having 1 to 3 carbon atoms substituted by 1 to 3 halogenatoms, or an imidazolyl group), or R¹ and R² together with the nitrogenatom to which they are attached form a group represented by the formula:

(wherein W is CH, a carbon atom or a nitrogen atom, Y is a group of—C(═O)— or —(CH₂)_(m)— (wherein m is 1 or 2), R¹⁵ and R¹⁶ are each ahydrogen atom or when W is a carbon atom, R¹⁵ and R¹⁶ together with thecarbon atoms to which they are attached form a benzene ring or anaphthalene ring,

R³ is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms or acinnamyl group,

R⁴ is a hydrogen atom, an acetyl group, an ethylsuccinyl group or anicotinoyl group,

A is a group represented by the formula:

—OC(═O)—R¹⁷,

—OC(═O)—CH₂—R¹⁷,

—OC(═O)—NH—R¹⁷,

—O—R¹⁷ or

—OC(═O)—O—R¹⁷

(wherein R¹⁷ is a phenyl group, a pyridyl group, a quinolyl group, orthose groups which are each substituted by 1 to 3 members selected bythe group consisting of an alkyl group having 1 to 5 carbon atoms, anitro group, an alkoxy group having 1 to 5 carbon atoms and a halogenatom), and

R⁵ and R⁶ are each a hydrogen atom or an alkyl group having 1 to 5carbon atoms] or a pharmaceutically acceptable salt thereof.

In the present invention, the alkyl group having 1 to 5 carbon atomsrefers to a straight or branched chain alkyl group, for example, amethyl group, an ethyl group, a propyl group, an isopropyl group, abutyl group, a tert-butyl group or a pentyl group. The alkoxy grouphaving 1 to 5 carbon atoms refers to a straight or branched chain alkoxygroup, preferably a methoxy group or an ethoxy group. The halogen atomrefers to a fluorine atom, a chlorine atom, a bromine atom or an iodineatom. Examples of the 6-membered ring and the condensed ring in thegroup represented by Formula (a) are a benzene ring, a naphthalene ring,a pyridine ring, a quinoline ring and an isoquinoline ring. Examples ofthe 5-membered ring and the condensed ring in the group represented byFormula (b) are a furan ring, a thiophene ring, a pyrrole ring, abenzofuran ring, a benzothiophene ring and an indole ring. Examples ofthe 5-membered ring, the 6-membered ring and the condensed ring in thegroup represented by Formula (c) are a pyrrolidine ring, a piperidinering, an imidazolidine ring, an isoindoline ring, a1,2,3,4-tetrahydroisoquinoline ring and a 2-oxoisoindoline ring.

The amino group substituted by 1 or 2 alkyl groups having 1 to 3 carbonatoms as defined for R⁷, R⁸ and R⁹ is preferably an amino groupsubstituted by methyl group(s), more preferably a dimethylamino group.

The alkyl group having 1 to 3 carbon atoms substituted by 1 to 3 halogenatoms as defined for R⁷, R⁸, R⁹ and R¹⁴ is preferably an alkyl groupsubstituted by fluorine atom(s), more preferably a methyl groupsubstituted by fluorine atom(s), and most preferably a trifluoromethylgroup.

The pharmaceutically acceptable salt refers to a salt used inchemotherapy or prophylaxis of bacterially infectious diseases, forexample, a salt with acetic acid, propionic acid, butyric acid, formicacid, trifluoroacetic acid, maleic acid, tartaric acid, citric acid,stearic acid, succinic acid, ethylsuccinic acid, lactobionic acid,gluconic acid, glucoheptonic acid, benzoic acid, methanesulfonic acid,ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, laurylsulfuric acid, malic acid, aspartic acid,glutaminic acid, adipic acid, cysteine, N-acetylcysteine, hydrochloricacid, hydrobromic acid, phosphoric acid, sulfuric acid, hydroiodic acid,nicotinic acid, oxalic acid, picric acid, thiocyanic acid, undecanicacid, polyacrylate or carboxyvinyl polymer.

The compounds of the present invention can be prepared, for example, bythe following methods, but not limited thereto.

Step (1);10,11-Anhydro-2′,4″-di-O-acetyl-12-O-imidazolylcarbonyl-6-O-methylerythromycinA described in EP patent No. 638584 is reacted with an agent representedby the formula:

(wherein, R⁵, R⁶ and n are as defined above) in an inert solvent at atemperature of from −30° C. to 100° C. The resulting 11,12-cycliccarbamate compound is reacted in a lower alcohol or an aqueous loweralcohol, if desired, in the presence of a base such as sodiumbicarbonate, at a temperature of from 0° C. to 100° C. to remove theprotective group at the 2′-position, and whereby there is obtained acompound of Formula (a) (wherein R⁵, R⁶ and n are as defined above).Examples of the inert solvent to be used herein are acetonitrile,tetrahydrofuran, N,N-dimethylformamide, dioxane, ethyl acetate,N-methylpyrrolidone, an aqueous solution thereof and a mixture thereof.Examples of the lower alcohol to be used herein are methanol, ethanoland propyl alcohol.

Step (2); The compound of Formula (a) is reacted with a slight excessamount of an aldehyde compound (e.g. pyridylaldehyde) relative to thecompound of Formula (a) in a lower alcohol in the presence of an acidsuch as acetic acid at a temperature of from −30° C. to 60° C. to give acompound of Formula (b) (wherein R⁵, R⁶, R¹⁴ and n are as definedabove). When the reaction is carried out, addition of a reductant in thesystem gives a compound of Formula (c) (wherein R¹, R⁵, R⁶ and n are asdefined above). The lower alcohol is the same as used in Step (1).Examples of the reductant to be used herein are sodium borohydride,sodium cyanoborohydride and sodium triacetoxyborohydride.

Step (3); The compound of Formula (c) is reacted in the same manner asin Step (2) using formaldehyde, acetaldehyde, quinolylaldehyde,furaldehyde, thiophenecarboxaldehyde or pyridylaldehyde to give acompound of Formula (d) (wherein R¹, R², R⁵, R⁶ and n are as definedabove).

Step (4); The compound of Formula (d) is reacted with an acid such ashydrochloric acid for removal of the sugar at the 3-position, and thenprotected with, for example, an acetyl group at the 2′-position in anordinary manner to give a compound of Formula (e) (wherein R¹, R², R⁴,R⁵, R⁶ and n are as defined above).

Step (5); The compound of Formula (e) is reacted using a reagentrepresented by the formula:

R¹⁷—CH₂COOH

(wherein R¹⁷ is as defined above) and an activating agent thereof in aninert solvent in the presence of a base such as 4-dimethylaminopyridineat a temperature of from −30° C. to 30° C. to give a 3-ester compound,which is then subjected to the same deprotection at the 2′-position asin Step (1) in a lower alcohol or an aqueous lower alcohol to give acompound of Formula (f) which is a compound of the present invention.Examples of the activating agent to be used herein are1,3-dicyclohexylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and pivaloylchloride. Examples of the inert solvent to be used are dichloromethane,dichloroethane, acetone, pyridine, ethyl acetate and tetrahydrofuran.

Step (6); The compound of Formula (b) is treated in the same manners asin Step (4) and Step (5), successively, to give a compound of Formula(g) (wherein R⁵, R⁶, R¹⁴, R¹⁷ and n are as defined above).

Step (7); The compound of Formula (a) is treated in the same manner asin Step (4) for removal of the sugar at the 3-position, and then theprimary amino group and the hydroxyl group at the 2′-position areprotected with benzyloxycarbonyl groups in an ordinary manner to give acompound of Formula (h) (wherein R⁵, R⁶ and n are as defined above).

Step (8); The compound of Formula (h) is treated in the same manner asin Step (5) for esterification at the 3-position, and then thebenzyloxycarbonyl groups are removed by an ordinary manner such ascatalytic hydrogenolysis to give a compound of Formula (i).

Step (9); The compound of Formula (i) is reacted with an acid halide inan inert solvent in the presence of a base such as pyridine or4-dimethylaminopyridine to give a compound of Formula (j) (wherein R¹,R⁵, R⁶, R¹⁷ and n are as defined above) which is a compound of thepresent invention. The inert solvent herein is the same as used in Step(5), and examples of the acid halide are benzoyl chloride, nicotinoylchloride and quinolinoyl chloride.

The compounds of the present invention can be administered orally orparenterally in the various preparation forms for the purpose of theapplication based on the pharmacological properties. The pharmaceuticalcomposition of the present invention can be prepared by homogeneouslymixing an effective amount of the compound of the present invention inthe free form or in the form of an acid addition salt thereof, with apharmaceutically acceptable carrier, which may be various formsaccording to the desired dosage forms. Examples of the dosage forms inthe present invention are tablets, capsules, powders, troches,ointments, suspensions, suppositories and injections, all of which canbe prepared according to conventional preparation techniques.

The dose of the compound of the present invention to adults is from 100to 1000 mg/day in 2 or 3 divided doses. This dose can be increased ordecreased depending on the age, body weight and conditions of thepatient.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is illustrated in more detail by the followingExamples.

EXAMPLE 1

Synthesis of11-{2-[N,N-bis(3-pyridylmethyl)amino]ethyl}amino-11-deoxy-3-O-(3-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

(1) To a solution of 70.0 g (77 mmoles) of10,11-anhydro-2′,4″-di-O-acetyl-12-O-imidazolylcarbonyl-6-O-methylerythromycinA described in European Patent No. 638584 in 1 L of acetonitrile wasadded 30.0 ml (231 mmoles) of ethylenediamine at room temperature,followed by stirring overnight. The reaction solution was evaporatedunder reduced pressure and dissolved in 1 L of methanol, followed byheating under reflux for 4 hours. After evaporation of the solvent,purification by silica gel column chromatography(chloroform:methanol:aqueous ammonia=20:1:0.1) gave 67.0 g (yield: 97%)of the 11-(2-aminoethyl)amine compound.

(2) To a solution of 5.0 g (6.0 mmoles) of the compound obtained in theabove (1) in 60 ml of methanol were added 2.8 ml (30 mmoles) ofnicotinealdehyde and 3.9 ml (61 mmoles) of acetic acid, then 1.9 g (30mmoles) of sodium cyanoborohydride under ice-cooling. The reactionsolution was heated to 60° C. under reflux for 4 hours.

The reaction solution was adjusted to pH 10 with 4N sodium hydroxide,and extracted with chloroform. The organic layer was dried overanhydrous magnesium sulfate, followed by evaporation of the solventunder reduced pressure. The residue was purified by silica gel columnchromatography (chloroform:methanol:aqueous ammonia=20:1:0.1) to give2.3 g (yield: 38%) of the11-{2-[N,N-bis(3-pyridylmethyl)amino]ethyl}amino compound, a solution ofwhich in 30 ml of 1N aqueous hydrochloric acid solution was stirred atroom temperature overnight. After the reaction, the mixture was madebasic with 4N aqueous sodium hydroxide solution, and extracted withchloroform. The organic layer was dried over anhydrous magnesiumsulfate, followed by evaporation of the solvent under reduced pressure.The residue was purified by silica gel column chromatography(chloroform:methanol:aqueous ammonia=20:1:0.1) to give 1.7 g (yield:87%) of the 3-hydroxyl compound.

(3) To a solution of 1.7 g (2.0 mmoles) of the compound obtained in theabove (2) in 20 ml of methylene chloride was added 0.35 ml (3.1 mmoles)of acetic anhydride at room temperature, followed by stirring overnight.The reaction solution was made basic with a saturated aqueous sodiumbicarbonate solution and extracted with chloroform. The chloroform layerwas washed with distilled water and an aqueous sodium chloride solution.The organic layer was dried over anhydrous magnesium sulfate, followedby evaporation of the solvent under reduced pressure to give 1.7 g ofthe 2′-O-acetyl compound.

(4) To a solution of 0.50 g (0.57 mmole) of the compound obtained in theabove (3) in 10 ml of methylene chloride were successively added 0.20 g(1.1 mmoles) of 3-pyridylacetic acid hydrochloride, 0.21 g (1.1 mmoles)of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.05g (0.41 mmole) of 4-dimethylaminopyridine under ice-cooling, followed bystirring at room temperature for 1.5 hours. The reaction solution wasmade basic with 2N sodium hydroxide and extracted with chloroform. Theorganic layer was dried over anhydrous magnesium sulfate, followed byevaporation of the solvent under reduced pressure. The residue wasdissolved in 14 ml of methanol, and heated under reflux for 2 hours.After evaporation of the solvent, purification by silica gel columnchromatography (chloroform:methanol:aqueous ammonia=20:1:0.1) gave 0.30g (yield: 55%) of the title compound.

Mass (FAB; 3-NBA) m/z: 959 [M+H]⁺; ¹H-NMR (500 MHz, CDCl₃) δ(ppm): 0.77(t, 3H, J=7.3 Hz, H15), 2.27(s, 6H, NMe₂), 2.83 (s, 3H, 6-OMe), 4.99 (d,1H, J=11.0 Hz, H3), 5.01 (m, 1H, H13).

EXAMPLE 2

Synthesis of11-{2-[N,N-bis(3-pyridylmethyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

To a solution of 0.41 g (0.47 mmole) of the compound obtained in Example1(3) in 10 ml of methylene chloride were successively added 0.16 g (0.93mmole) of 2-pyridylacetic acid hydrochloride, 0.18 g (0.93 mmole) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.05 g(0.41 mmole) of 4-dimethylaminopyridine under ice-cooling, followed bystirring at room temperature for 1.5 hours. The reaction solution wasmade basic with 2N sodium hydroxide and extracted with chloroform. Theorganic layer was dried over anhydrous magnesium sulfate, followed byevaporation of the solvent under reduced pressure. The residue wasdissolved in 10 ml of methanol, and heated under reflux for 2 hours.After evaporation of the solvent, purification by silica gel columnchromatography (chloroform:methanol:aqueous ammonia=20:1:0.1) gave 0.30g (yield: 66%) of the title compound.

Mass (FAB; 3-NBA) m/z: 959 [M+H]⁺; ¹H-NMR (500 MHz, CDCl₃) δ(ppm): 0.77(t, 3H, J=7.3 Hz, H15), 2.29 (s, 6H, NMe₂), 2.84 (s, 3H, 6-OMe), 5.00(d, 1H, J=11.6 Hz, H3), 5.01 (dd, 1H, J=11.0, 2.4 Hz, H13).

EXAMPLE 3

Synthesis of11-{2-[N-methyl-N-(3-pyridylmethyl)amino]ethyl}amino-11-deoxy-3-O-(3-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

(1) To a solution of 20.0 g (22.4 mmoles) of the compound obtained inExample 1(1) in 200 ml of methanol were added 2.8 ml (29.1 mmoles) ofnicotinealdehyde and 7.3 ml (112 mmoles) of acetic acid, then 2.8 g(44.8 mmoles) of sodium cyanoborohydride under ice-cooling. Thetemperature was turned to room temperature, followed by stirring for 4hours. The reaction solution was made basic with 4N sodium hydroxide andextracted with diethyl ether. The organic layer was dried over anhydrousmagnesium sulfate, followed by evaporation of the solvent under reducedpressure. The residue was dissolved in 200 ml of ethanol, and then 30.0ml (224 mmoles) of 37% aqueous formaldehyde solution and 11.0 ml (224mmoles) of 90% aqueous formic acid solution were added thereto, followedby heating under reflux for 3.5 hours. The reaction solution wasevaporated under reduced pressure, made basic with 4N sodium hydroxideand extracted with chloroform. The organic layer was dried overanhydrous magnesium sulfate, followed by evaporation of the solventunder reduced pressure. The residue was purified by silica gel columnchromatography (chloroform:methanol:aqueous ammonia=20:1:0.1) to give21.0 g (yield: 97%) of the11-{2-[N-methyl-N-(3-pyridylmethyl)amino]ethyl}amino compound.

(2) A solution of the compound obtained in the above (1) in 200 ml of 1Naqueous hydrochloric acid solution was stirred at room temperatureovernight, made basic with 4N aqueous sodium hydroxide solution, andextracted with chloroform. The organic layer was dried over anhydrousmagnesium sulfate, followed by evaporation of the solvent under reducedpressure. The residue was purified by silica gel column chromatography(chloroform:methanol:aqueous ammonia=20:1:0.1) to give 13.0 g (yield:82%) of the 3-hydroxyl compound.

(3) Following the same procedure as in Example 1(3) using 13.0 g (17.1mmoles) of the compound obtained in the above (2), there was obtained12.7 g of the 2′-O-acetyl compound.

(4) Following the same procedure as in Example 1(4) using 0.25 g (0.31mmole) of the compound obtained in the above (3), there was obtained0.15 g (yield: 55%) of the title compound.

Mass (FAB; 3-NBA) m/z: 882 [M+H]⁺; ¹H-NMR (500 MHz, CDCl₃) δ(ppm): 0.71(t, 3H, J=7.32 Hz, H15), 2.18 (s, 3H), 2.28 (s, 6H, NMe₂), 3.02 (s, 3H,6-OMe), 5.04 (d, 1H, J=11.0 Hz, H3), 5.18 (dd, 1H, J=11.0, 2.4 Hz, H13).

EXAMPLE 4

Synthesis of11-{2-[N-methyl-N-(3-pyridylmethyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Following the same procedure as in Example 2 using 0.31 g (0.39 mmole)of the compound obtained in Example 3(3), there was obtained 0.25 g(yield: 73%) of the title compound.

Mass (FAB; 3-NBA) m/z: 882 [M+H]⁺; ¹H-NMR (500 MHz, CDCl₃) δ(ppm): 0.72(t, 3H, J=7.32 Hz, H15), 2.19 (s, 3H), 2.29 (s, 6H, NMe₂), 3.02 (s, 3H,6-OMe), 5.06 (d, 1H, J=11.0 Hz, H3), 5.19 (dd, 1H, J=11.0, 2.4 Hz, H13).

EXAMPLE 5

Synthesis of11-{2-[N,N-bis(2-pyridylmethyl)amino]ethyl}amino-11-deoxy-3-O-(3-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

(1) Following the same procedure as in Example 1(2) using 2.08 g (2.5mmoles) of the compound obtained in Example 1(1) and 0.47 ml (5.0mmoles) of 2-pyridinecarboxaldehyde, there was obtained 0.90 g (yield:43%) of the 3-hydroxyl compound.

(2) Following the same procedure as in Example 1(3) using 0.77 g (0.92mmole) of the compound obtained in the above (1), there was obtained0.80 g (yield: 99%) of the 2′-O-acetyl compound.

(3) Following the same procedure as in Example 1(4) using 0.39 g (0.44mmole) of the compound obtained in the above (2), there was obtained0.23 g (yield: 55%) of the title compound.

Mass (FAB; 3-NBA) m/z: 959 [M+H]⁺; ¹H-NMR (500 MHz, CDCl₃) δ(ppm); 0.73(t, 3H, J=7.32 Hz, H15), 2.27 (s, 6H, NMe₂), 2.86 (s, 3H, 6-OMe), 4.99(d, 1H, J=11.6 Hz, H3), 5.01 (dd, 1H, J=11.0, 2.4 Hz, H13).

EXAMPLE 6

Synthesis of11-{2-[N,N-bis(2-pyridylmethyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Following the same procedure as in Example 2 using 0.40 g (0.44 mmole)of the compound obtained in Example 5(2), there was obtained 0.40 g(yield: 79%) of the title compound.

Mass (FAB; 3-NBA) m/z: 959 [M+H]⁺; ¹H-NMR (500 MHz, CDCl₃) δ(ppm): 0.73(t, 3H, J=7.32 Hz, H15), 2.29 (s, 6H, NMe₂), 2.85 (s, 3H, 6-OMe), 5.00(d, 1H, J=11.6 Hz, H3), 5.01 (dd, 1H, J=11.0, 2.4 Hz, H13).

EXAMPLE 7

Synthesis of11-{2-[N-methyl-N-(2-pyridylmethyl)amino]ethyl}amino-11-deoxy-3-O-(3-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

(1) Following the same procedure as in Example 3(1) using 0.34 ml (3.6mmoles) of 2-pyridinecarboxaldehyde in place of nicotinealdehyde and3.00 g (3.6 mmoles) of the compound obtained in Example 1(1), there wasobtained 1.43 g (yield: 41%) of the11-{2-[N-methyl-N-(2-pyridylmethyl)amino]ethyl}amino compound.

(2) Following the same procedure as in Example 3(2) using 1.40 g (1.46imoles) of the compound obtained in the above (1), there was obtained1.03 g (yield: 93%) of the 3-hydroxyl compound.

(3) Following the same procedure as in Example 1(3) using 0.88 g (1.20mmoles) of the compound obtained in the above (2), there was obtained0.83 g (yield: 97%) of the 2′-O-acetyl compound.

(4) Following the same procedure as in Example 1(4) using 0.35 g (0.44mmole) of the compound obtained in the above (3), there was obtained0.33 g (yield: 85%) of the title compound.

Mass (FAB; 3-NBA) m/z: 882 [M+H]⁺; ¹H-NMR (500 MHz, CDCl₃) δ(ppm): 0.68(t, 3H, J=7.32 Hz, H15), 2.27 (s, 3H), 2.30 (s, 6H, NMe₂), 3.02 (s, 3H,6-OMe), 5.03 (d, 1H, J=11.0 Hz, H3), 5.17 (dd, 1H, J=11.0, 2.4 Hz, H13).

EXAMPLE 8

Synthesis of11-{2-[N-methyl-N-(2-pyridylmethyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Following the same procedure as in Example 2 using 0.35 g (0.44 mmole)of the compound obtained in Example 7(3), there was obtained 0.30 g(yield: 77%) of the title compound.

Mass (FAB; 3-NBA) m/z: 882 [M+H]⁺; ¹H-NMR (500 MHz, CDCl₃) δ(ppm): 0.69(t, 3H, J=7.32 Hz, H15), 2.27 (s, 3H), 2.29 (s, 6H, NMe₂), 3.02 (s, 3H,6-OMe), 5.05 (d, 1H, J=11.0 Hz, H3), 5.17 (dd, 1H, J=11.0, 2.4 Hz, H13).

EXAMPLE 9

Synthesis of11-{2-[N-methyl-N-(4-quinolylmethyl)amino]ethyl}amino-11-deoxy-3-O-(3-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

(1) Following the same procedure as in Example 3(1) using 1.2 g (7.8mmoles) of 4-quinolinecarboxaldehyde in place of nicotinealdehyde and5.80 g (6.5 mmoles) of the compound obtained in Example 1(1), there wasobtained 3.70 g (yield: 56%) of the11-{2-[N-methyl-N-(4-quinolylmethyl)amino]ethyl}amino compound.

(2) Following the same procedure as in Example 3(2) using 3.60 g (3.5mmoles) of the compound obtained in the above (1), there was obtained2.40 g (yield: 80%) of the 3-hydroxyl compound.

(3) Following the same procedure as in Example 1(3) using 2.10 g (2.5mmoles) of the compound obtained in the above (2), there was obtained2.20 g (yield: 99%) of the 2′-O-acetyl compound.

(4) Following the same procedure as in Example 1(4) using 0.70 g (0.82mmole) of the compound obtained in the above (3), there was obtained0.36 g (yield: 47%) of the title compound.

Mass (FAB; 3-NBA) m/z: 932 [M+H]⁺.

EXAMPLE 10

Synthesis of11-{2-[N-methyl-N-4-quinolylmethyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Following the same procedure as in Example 2 using 0.70 g (0.82 mmole)of the compound obtained in Example 9(3), there was obtained 0.33 g(yield: 45%) of the title compound.

Mass (FAB; 3-NBA) m/z: 932 [M+H]⁺.

EXAMPLE 11

Synthesis of11-{3-[N-methyl-N-(3-pyridylmethyl)amino]propyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

(1) Carrying out the same reaction as in Example 1(1) using 14.6 g (16mmoles) of10,11-anhydro-2′,4″-di-O-acetyl-12-O-imidazolylcarbonyl-6-O-methylerythromycinA and 4.0 ml (48 mmoles) of 1,3-diaminopropane, there was obtained 10.14g (yield: 73%) of the 11-(3-aminopropyl)amino compound.

Mass (FAB) m/z: 872 [M+H]⁺.

(2) Carrying out the same reactions as in Examples 3(1) and 3(2) using5.8 g (6.7 mmoles) of the compound obtained in the above (1), there wasobtained 2.81 g (yield: 54%) of the 3-hydroxyl compound.

Mass (FAB) m/z: 777 [M+H]⁺.

(3) Carrying out the same reaction as in Example 1(3) using 2.30 g (3.0mmoles) of the compound obtained in the above (2), there was obtained2.22 g of the 2′-O-acetyl compound.

(4) Carrying out the same reaction as in Example 2 using 0.68 g (0.83mmole) of the compound obtained in the above (3), there was obtained0.58 g (yield: 78%) of the title compound.

Mass (FAB) m/z: 896 [M+H]⁺.

EXAMPLE 12

Synthesis of11-{3-[N-methyl-N-(3-pyridylmethyl)amino]propyl}amino-11-deoxy-3-O-(3-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Carrying out the same reaction as in Example 1(4) using 0.67 g (0.82mmole) of the compound obtained in Example 11(3), there was obtained0.46 g (yield: 63%) of the title compound.

Mass (FAB) m/z: 896 [M+H]⁺.

EXAMPLE 13

Synthesis of11-{3-[N,N-bis(3-pyridylmethyl)amino]propyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

(1) Carrying out the same N,N-bis(3-pyridylmethyl)amination as inExample 1(2) using 3.27 g (3.8 moles) of the compound obtained inExample 11(1), there was obtained 2.85 g (yield: 72%) of4″-O-acetyl-11-{3-[N,N-bis(3-pyridylmethyl)amino]propyl}amino-11-deoxy-6-O-methylerythromycinA 11,12-cyclic carbamate.

Mass (FAB) m/z; 1054 [M+H]⁺.

(2) A solution of 2.51 g (2.38 mmoles) of the compound obtained in theabove (1) in 50 ml of 1N aqueous hydrochloric acid solution was stirredat room temperature overnight, made basic with 2N aqueous sodiumhydroxide solution and then extracted with chloroform. The organic layerwas dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure to give 1.85 g of the residue, whichwas then purified by silica gel column chromatography(chloroform:methanol:aqueous ammonia=15:1:0.1) to give 1.18 g (yield:58%) of the 3-hydroxyl compound.

Mass (FAB) m/z: 854 [M+H]⁺.

(3) Carrying out the same reaction as in Example 1(3) using 1.04 g (1.22mmoles) of the compound obtained in the above (2), there was obtained1.15 g of the 2′-O-acetyl compound.

(4) Carrying out the same reaction as in Example 2 using 0.59 g (0.66mmole) of the compound obtained in the above (3), there was obtained0.42 g (yield: 66%) of the title compound.

Mass (FAB) m/z: 973 [M+H]⁺.

EXAMPLE 14

Synthesis of11-{3-[N,N-bis(3-pyridylmethyl)amino]propyl}amino-11-deoxy-3-O-(3-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Carrying out the same reaction as in Example 1(4) using 0.54 g (0.6mmole) of the compound obtained in Example 13(3), there was obtained0.25 g (yield: 42%) of the title compound.

Mass (FAB) m/z: 973 [M+H]⁺.

EXAMPLE 15

Synthesis of11-{3-[N-methyl-N-(2-pyridylmethyl)amino]propyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

(1) Carrying out the same reaction as in Example 3(1) using 4.91 g (5.6mmoles) of the compound obtained in Example 11(1), there was obtained2.08 g (yield: 38%) of the11-{3-[N-methyl-N-(2-pyridylmethyl)amino]propyl}amino compound.

Mass (FAB) m/z: 977 [M+H]⁺.

(2) 2.08 g (2.1 mmoles) of the compound obtained in the above (1) wastreated in the same manner as in Example 13(2) for removal of thecladinose moiety, followed by the same reaction as in Example 1(3) togive 1.45 g of the 2′-O-acetyl compound.

(3) Carrying out the same reaction as in Example 2 using 0.51 g (0.63mmole) of the compound obtained in the above (2), there was obtained0.31 g (yield: 55%) of the title compound.

Mass (FAB) m/z: 896 [M+H]⁺.

EXAMPLE 16

Synthesis of11-{3-[N-methyl-N-(2-pyridylmethyl)amino]propyl}amino-11-deoxy-3-O-(3-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Carrying out the same reaction as in Example 1(4) using 0.51 g (0.63mmole) of the compound obtained in Example 15(2), there was obtained0.24 g (yield: 43%) of the title compound.

Mass (FAB) m/z: 896 [M+H]⁺.

EXAMPLE 17

Synthesis of11-{3-[N,N-bis(2-pyridylmethyl)amino]propyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

(1) Following the same procedures as in Examples 1(2) and 3(2) using5.04 g(5.78 mmoles) of the compound obtained in Example 11(1) and 2.7 ml(28.4 mmoles) of 2-pyridinecarboxaldehyde, there was obtained 3.35 g(yield: 68%) of11-{3-[N,N-bis(2-pyridylmethyl)-amino]propyl}amino-11-deoxy-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate.

(2) Carrying out the same reaction as in Example 1(3) using 3.1 g (3.63mmoles) of the compound obtained in the above (1), there was obtained3.18 g (yield: 98%) of the 2′-O-acetyl compound.

(3) Carrying out the same reaction as in Example 2 using 1.5 g (1.67mmoles) of the compound obtained in the above (2), there was obtained0.88 g (yield: 54%) of the title compound.

Mass (FAB) m/z: 973 [M+H]⁺.

EXAMPLE 18

Synthesis of11-{3-[N,N-bis(3-pyridylmethyl)amino]propyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Carrying out the same reaction as in Example 1(4) using 1.5 g (1.67mmoles) of the compound obtained in Example 17(2), there was obtained1.47 g (yield: 90%) of the title compound.

Mass (FAB) m/z: 973 [M+H]⁺.

EXAMPLE 19

Synthesis of11-{5-[N-methyl-N-(3-pyridylmethyl)amino]pentyl}amino-11-deoxy-3-O-(3-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

(1) Carrying out the same reaction as in Example 1(1) using 2.0 g (2.2mmoles) of10,11-anhydro-2′,4″-di-O-acetyl-12-O-imidazolylcarbonyl-6-O-methylerythromycinA and 0.52 ml (4.4 mmoles) of 1,5-diaminopentane, there was obtained1.20 g (yield: 61%) of the4″-O-acetyl-11-(5-aminopentyl)amino-11-deoxy-6-O-methylerythromycin A11,12-cyclic carbamate compound.

Mass (FAB) m/z: 900 [M+H]⁺.

(2) Carrying out the same reactions as in Examples 3(1), 3(2), 1(3) and1(4) using 1.0 g (1.11 mmoles) of the compound obtained in the above(1), there was obtained 0.36 g of the title compound.

Mass (FAB) m/z: 924 [M+H]⁺.

EXAMPLE 20

Synthesis of11-[2-(N-methyl-N-benzylamino)ethyl]amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

(1) Carrying out the same reaction as in Example 3(1) using 2.4 g (2.8mmoles) of the compound obtained in Example 1(1) and 0.29 ml (2.85mmoles) of benzaldehyde, there was obtained 1.49 g (yield: 57%) of the11-[2-(N-methyl-N-benzylamino)ethyl]amino compound.

Mass (FAB) m/z: 920 [M+H]⁺

(2) Carrying out the same reactions as in Examples 3(2), 3(3) and 2,successively, using 0.5 g (0.54 mmole) of the compound obtained in theabove (1), there was obtained 0.31 g (yield: 65%) of the title compound.

Mass (FAB) m/z: 881 [M+H]⁺.

EXAMPLE 21

Synthesis of11-{2-[N-methyl-N-(3-pyridylmethyl)amino]ethyl}amino-11-deoxy-3-O-(4-nitrophenyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Following the same procedure as in Example 2 using 0.60 g (0.75 mmole)of the compound obtained in Example 3(3) and p-nitrophenylacetic acid,there was obtained 0.31 g (yield: 45%) of the title compound.

Mass (IonSpray) m/z: 926.5 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.71(t, 3H, J=7.25 Hz, H15), 2.18 (s, 3H, NMe), 2.27 (s, 6H, NMe₂), 3.02(s,3H, 6-OMe), 7.53 (m, 2H), 8.21 (m, 2H).

EXAMPLE 22

Synthesis of11-{2-[N-methyl-N-(3-pyridylmethyl)amino]ethyl}amino-11-deoxy-3-O-nicotinoyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Following the same procedure as in Example 2 using 0.60 g (0.75 mmole)of the compound obtained in Example 3(3) and nicotinic acid, there wasobtained 0.50 g (yield; 75%) of the title compound.

Mass (IonSpray) m/z: 868.5 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.76(t, 3H, J=7.26 Hz, H15), 2.10 (s, 6H, NMe₂), 2.22 (s, 3H, NMe), 3.09(s,3H, 6-OMe), 5.26 (dd, 1H, J=11.0, 2.0 Hz), 5.33 (d, 1H, J=11.2 Hz).

EXAMPLE 23

Synthesis of11-{2-[N-methyl-N-(3-pyridylmethyl)amino]ethyl}amino-11-deoxy-3-O-picolinoyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Following the same procedure as in Example 2 using 0.60 g (0.75 mmole)of the compound obtained in Example 3(3) and picolinic acid, there wasobtained 0.21 g (yield: 32%) of the title compound.

Mass (IonSpray) m/z: 868.5 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.75(t, 3H, J=7.44 Hz, H15), 2.12 (s, 6H, NMe₂), 2.22 (s, 3H, NMe), 3.09 (s,3H, 6-OMe), 5.26 (dd, 1H, J=11.2, 2.1 Hz), 5.36 (d, 1H, J=11.3 Hz).

EXAMPLE 24

Synthesis of11-{2-[N-methyl-N-(3-pyridylmethyl)amino]ethyl}amino-11-deoxy-3-O-isonicotinoyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Following the same procedure as in Example 2 using 0.60 g (0.75 mmole)of the compound obtained in Example 3(3) and isonicotinic acid, therewas obtained 0.37 g (yield: 57%) of the title compound.

Mass (IonSpray) m/z: 868.5 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.76(t, 3H, J=7.26 Hz, H15), 2.10 (s, 6H, NMe₂), 2.22 (s, 3H, NMe), 3.08 (s,3H, 6-OMe), 5.26 (dd, 1H, J=11.2, 2.1 Hz), 5.31 (d, 1H, J=11.2 Hz), 7.95(m, 2H), 8.85 (m, 2H).

EXAMPLE 25

Synthesis of11-{2-[N-methyl-N-(4-nitrobenzyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

(1) Following the same procedure as in Example 3(1) using 0.61 g (4.0mmoles) of 4-nitrobenzaldehyde in place of nicotinealdehyde and 2.80 g(3.4 mmoles) of the compound obtained in Example 1(1), there wasobtained the 11-{2-[N-methyl-N-(4-nitrobenzyl)amino]ethyl}aminocompound, followed by the same procedure as in Example 3(2) to give 0.90g (yield: 32%) of the 3-hydroxyl compound.

(2) Following the same procedure as in Example 1(3) using 0.70 g (0.84mmole) of the compound obtained in the above (1), there was obtained0.75 g (yield: 99%) of the 2′-O-acetyl compound.

(3) Following the same procedure as in Example 2 using 0.50 g (0.57mmole) of the compound obtained in the above (2), there was obtained0.35 g (yield: 66%) of the title compound.

Mass (IonSpray) m/z: 926.6 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.70(t, 3H, J=7.26 Hz, H15), 2.20 (s, 3H, NMe), 2.30 (s, 6H, NMe₂), 3.02 (s,3H, 6-OMe), 7.50 (m, 2H), 8.13 (m, 2H).

EXAMPLE 26

Synthesis of11-{2-[N-methyl-N-(4-aminobenzyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

To a solution of 0.50 g (0.54 mmole) of the compound obtained in Example22 in 5.0 ml of methanol were added 0.26 g (1.1 mmoles) of nickelchloride hexahydrate and 82 mg (2.2 mmoles) of sodium borohydride underice-cooling, followed by stirring for 10 minutes. After the reaction,25% aqueous ammonia was added to the reaction mixture, followed byextraction with chloroform. The organic layer was washed with asaturated aqueous sodium chloride solution and dried over anhydrouspotassium carbonate, followed by evaporation of the solvent underreduced pressure. The residue was purified by silica gel columnchromatography (chloroform:methanol:aqueous ammonia=20:1:0.1) to give0.26 g (yield: 54%) of the title compound.

Mass (IonSpray) m/z: 896.6 [M+H]⁺; ¹H-NMR (500 MHz, CDCl₃) δ(ppm): 0.76(t, 3H, J=7.3 Hz, H15), 2.18 (s, 3H, NMe), 2.29 (s, 6H, NMe₂), 2.97 (s,3H, 6-OMe), 6.61 (m, 2H), 7.08 (m, 2H).

EXAMPLE 27

Synthesis of11-{2-[N-methyl-N-(4-methoxybenzyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

(1) Following the same procedure as in Example 3(1) using 0.44 ml (3.6mmoles) of 4-methoxybenzaldehyde in place of nicotinealdehyde and 3.00 g(3.6 mmoles) of the compound obtained in Example 1(1), there wasobtained the 11-{2-[N-methyl-N-(4-methoxybenzyl)amino]ethyl}aminocompound, followed by the same procedure as in Example 3(2) to give 1.89g (yield: 61%) of the 3-hydroxyl compound.

(2) Following the same procedure as in Example 1(3) using 1.80 g (2.1mmoles) of the compound obtained in the above (1), there was obtained1.80 g (yield: 95%) of the 2′-O-acetyl compound.

(3) Following the same procedure as in Example 2 using 0.80 g (0.88mmole) of the compound obtained in the above (2), there was obtained0.44 g (yield: 55%) of the title compound.

Mass (IonSpray) m/z: 911.6 [M+H]⁺; ¹H-NMR (500 MHz, CDCl₃) δ(ppm): 0.74(t, 3H, J=7.5 Hz, H15), 2.17 (s, 3H, NMe), 2.29 (s, 6H, NMe₂), 3.02 (s,3H, 6-OMe), 3.78 (s, 3H, Ph-OMe), 6.81 (m, 2H), 7.22 (m, 2H).

EXAMPLE 28

Synthesis of11-[2-(N-methyl-N-furfurylamino)ethyl]amino-11-deoxy-3-O-(2-pyridyl)-acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

(1) Following the same procedure as in Example 3(1) using 0.30 ml (3.6mmoles) of furfural in place of nicotinealdehyde and 3.00 g (3.6 mmoles)of the compound obtained in Example 1(1), there was obtained the11-[2-(N-methyl-N-furfurylamino)ethyl]amino compound, followed by thesame procedure as in Example 3(2) to give 1.20 g (yield: 40%) of the3-hydroxyl compound.

(2) Following the same procedure as in Example 1(3) using 1.10 g (1.3mmoles) of the compound obtained in the above (1), there was obtained1.0 g (yield: 89%) of the 2′-O-acetyl compound.

(3) Following the same procedure as in Example 2 using 0.50 g (0.58mmole) of the compound obtained in the above (2), there was obtained0.26 g (yield: 52%) of the title compound.

Mass (IonSpray) m/z: 871.5 [M+H]⁺; ¹H-NMR (500 MHz, CDCl₃) δ(ppm): 0.80(t, 3H, J=7.5 Hz, H15), 2.24 (s, 6H, NMe₂), 2.25 (s, 3H), 3.02 (s, 3H,NMe), 6.23 (m, 2H), 7.34 (m, 1H).

EXAMPLE 29

Synthesis of11-{2-[N-methyl-N-(4-pyridylmethyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

(1) Following the same procedure as in Example 3(1) using 0.34 ml (3.6mmoles) of isonicotinealdehyde in place of nicotinealdehyde and 3.00 g(3.6 mmoles) of the compound obtained in Example

1(1), there was obtained the11-{2-[N-methyl-N-(4-pyridylmethyl)amino]ethyl}amino compound, followedby the same procedure as in Example 3(2) to give 1.85 g (yield: 67%) ofthe 3-hydroxyl compound.

(2) Following the same procedure as in Example 1(3) using 1.60 g (2.1mmoles) of the compound obtained in the above (1), there was obtained1.56 g (yield: 92%) of the 2′-O-acetyl compound.

(3) Following the same procedure as in Example 2 using 0.50 g (0.62mmole) of the compound obtained in the above (2), there was obtained0.31 g (yield: 57%) of the title compound.

Mass (IonSpray) m/z: 882.6 [M+H]⁺; ¹H-NMR (500 MHz, CDCl₃) δ(ppm): 0.69(t, 3H, J=7.5 Hz, H15), 2.20 (s, 3H, NMe), 2.30 (s, 6H, NMe₂), 3.02 (s,3H, 6-OMe), 7.26 (m, 2H), 8.49 (m, 2H).

EXAMPLE 30

Synthesis of11-{2-[N-methyl-N-(2-thienylmethyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

(1) Following the same procedure as in Example 3(1) using 0.34 ml (3.6mmoles) of thiophene-2-aldehyde in place of nicotinealdehyde and 3.00 g(3.6 mmoles) of the compound obtained in Example 1(1), there wasobtained the 11-{2-[N-methyl-N-(2-thienylmethyl)amino]ethyl}aminocompound, followed by the same procedure as in Example 3(2) to give 1.34g (yield: 46%) of the 3-hydroxyl compound.

(2) Following the same procedure as in Example 1(3) using 1.20 g (1.5mmoles) of the compound obtained in the above (1), there was obtained1.24 g (yield: 99%) of the 2′-O-acetyl compound.

(3) Following the same procedure as in Example 2 using 0.50 g (0.62mmole) of the compound obtained in the above (2), there was obtained0.30 g (yield: 55%) of the title compound.

Mass (IonSpray) m/z: 887.5 [M+H]⁺; ¹H-NMR (500 MHz, CDCl₃) δ(ppm): 0.79(t, 3H, J=7.5 Hz, H15), 2.29 (s, 3H, NMe), 2.30 (s, 6H, NMe₂), 3.03 (s,3H, 6-OMe), 6.90 (m, 2H), 7.18 (m, 1H).

EXAMPLE 31

Synthesis of11-{2-[N-methyl-N-(3,4,5-trimethoxybenzyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

(1) Following the same procedure as in Example 3(1) using 0.71 g (3.6mmoles) of 3,4,5-trimethoxybenzaldehyde in place of nicotinealdehyde and3.00 g (3.6 mmoles) of the compound obtained in Example 1(1), there wasobtained the 11-{2-[N-methyl-N-(3,4,5-trimethoxybenzyl)amino]ethyl}aminocompound, followed by the same procedure as in Example 3(2) to give 1.99g (yield: 60%) of the 3-hydroxyl compound.

(2) Following the same procedure as in Example 1(3) using 1.67 g (1.8mmoles) of the compound obtained in the above (1), there was obtained1.39 g (yield: 80%) of the 2′-O-acetyl compound.

(3) Following the same procedure as in Example 2 using 0.50 g (0.52mmole) of the compound obtained in the above (2), there was obtained0.33 g (yield: 65%) of the title compound.

Mass (IonSpray) m/z: 971.6 [M+H]⁺; ¹H-NMR (500 MHz, CDCl₃) δ(ppm): 0.68(t, 3H, J=7.5 Hz, H15), 2.24 (s, 3H, NMe), 2.29 (s, 6H, NMe₂), 3.02 (s,3H, 6-OMe), 3.82 (s, 3H, Ph-OMe), 3.86 (s, 6H, Ph-OMe), 6.61 (s, 2H).

EXAMPLE 32

Synthesis of11-{2-[N-methyl-N-(4-tolylmethyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

(1) Following the same procedure as in Example 3(1) using 0.39 ml (3.3mmoles) of 4-tolualdehyde in place of nicotinealdehyde and 2.35 g (3.04mmoles) of the compound obtained in Example 1(1), there was obtained the11-{2-[N-methyl-N-(4-tolylmethyl)amino]ethyl}amino compound, followed bythe same procedure as in Example 3(2) to give 2.28 g (yield: 97%) of the3-hydroxyl compound.

(2) Following the same procedure as in Example 1(3) using 2.00 g (2.6mmoles) of the compound obtained in the above (1), there was obtained1.95 g (yield: 92%) of the 2′-O-acetyl compound.

(3) Following the same procedure as in Example 2 using 0.92 g (1.13mmoles) of the compound obtained in the above (2), there was obtained0.98 g (yield: 97%) of the title compound.

Mass (IonSpray) m/z: 895.6 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.75(t, 3H, J=7.26 Hz, H15), 2.18 (s, 3H, NMe), 2.29 (s, 6H, NMe₂), 2.31 (s,3H, PhMe), 3.02 (s, 3H, 6-OMe), 3.44 (d, 1H, J=13.0 Hz), 3.70 (d, 1H,J=13.0 Hz), 7.08 (m, 2H), 7.19 (m, 2H).

EXAMPLE 33

Synthesis of11-{2-[N-methyl-N-(2-tolylmethyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

(1) Following the same procedure as in Example 3(1) using 0.39 ml (3.3mmoles) of 2-tolualdehyde in place of nicotinealdehyde and 2.35 g (3.0mmoles) of the compound obtained in Example 1(1), there was obtained the11-{2-[N-methyl-N-(2-tolylmethyl)amino]ethyl}amino compound, followed bythe same procedure as in Example 3(2) to give 2.24 g (yield: 96%) of the3-hydroxyl compound.

(2) Following the same procedure as in Example 1(3) using 2.00 g (2.6mmoles) of the compound obtained in the above (1), there was obtained1.84 g (yield: 87%) of the 2′-O-acetyl compound.

(3) Following the same procedure as in Example 2 using 0.80 g (0.98mmole) of the compound obtained in the above (2), there was obtained0.48 g (yield: 50%) of the title compound.

Mass (IonSpray) m/z: 895.6 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.72(t, 3H, J=7.26 Hz, H15), 2.21 (s, 3H, NMe), 2.29 (s, 6H, NMe₂), 2.34 (s,3H, PhMe), 3.00 (s, 3H, 6-OMe), 3.51 (d, 1H, J=13.3 Hz), 3.62 (d, 1H,J=13.3 Hz), 7.10 (m, 3H), 7.32 (m, 1H).

EXAMPLE 34

Synthesis of11-{2-[N-methyl-N-(3-tolylmethyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 10 11,12-cyclic carbamate

(1) Following the same procedure as in Example 3(1) using 0.39 ml (3.3mmoles) of 3-tolualdehyde in place of nicotinealdehyde and 2.35 g (3.0mmoles) of the compound obtained in Example 1(1), there was obtained the11-{2-[N-methyl-N-(3-tolylmethyl)amino]ethyl}amino compound, followed bythe same procedure as in Example 3(2) to give 1.73 g (yield: 74%) of the3-hydroxyl compound.

(2) Following the same procedure as in Example 1(3) using 0.86 g (1.1mmoles) of the compound obtained in the above (1), there was obtained0.85 g (yield: 95%) of the 2′-O-acetyl compound.

(3) Following the same procedure as in Example 2 using 0.75 g (0.92mmole) of the compound obtained in the above (2), there was obtained0.45 g (yield: 55%) of the title compound.

Mass (IonSpray) m/z: 895.6 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.75(t, 3H, J=7.26 Hz, H15), 2.19 (s, 3H, NMe), 2.30 (s, 6H, NMe₂), 2.32 (s,3H, PhMe), 3.02 (s, 3H, 6-OMe), 3.44 (d, 1H, J=13.1 Hz), 3.70 (d, 1H,J=13.1 Hz), 7.01 (m, 1H), 7.13 (m, 3H).

EXAMPLE 35

Synthesis of11-{2-[N-methyl-N-(cyclohexylmethyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

(1) Following the same procedure as in Example 3(1) using 0.34 ml (3.3mmoles) of cyclohexanecarboxaldehyde in place of nicotinealdehyde and2.35 g (3.04 mmoles) of the compound obtained in Example 1(1), there wasobtained the 11-{2-[N-methyl-N-(cyclohexylmethyl)amino]ethyl}aminocompound, followed by the same procedure as in Example 3(2) to give 0.87g (yield: 37%) of the 3-hydroxyl compound.

(2) Following the same procedure as in Example 1(3) using 0.78 g (1.02mmoles) of the compound obtained in the above (1), there was obtained0.76 g (yield: 92%) of the 2′-O-acetyl compound.

(3) Following the same procedure as in Example 2 using 0.70 g (0.87mmole) of the compound obtained in the above (2), there was obtained0.57 g (yield: 74%) of the title compound.

Mass (IonSpray) m/z: 887.6 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.81(t, 3H, J=7.26 Hz, H15), 2.24 (s, 3H, NMe), 2.29 (s, 6H, NMe₂), 3.03 (s,3H, 6-OMe), 5.07 (d, 1H, J=11.2 Hz, H3), 5.13 (dd, 1H, J=11.2, 2.48 Hz,H13).

EXAMPLE 36

Synthesis of11-{2-[N-methyl-N-(1-methyl-2-pyrrolylmethyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

(1) Following the same procedure as in Example 3(1) using 0.36 g (3.3mmoles) of 1-methylpyrrole-2-carboxaldehyde in place of nicotinealdehydeand 2.35 g (3.04 mmoles) of the compound obtained in Example 1(1), therewas obtained the11-{2-[N-methyl-N-(N-methyl-2-pyrrolylmethyl)amino]ethyl}amino compound,followed by the same procedure as in Example 3(2) to give 0.57 g (yield:25%) of the 3-hydroxyl compound.

(2) Following the same procedure as in Example 1(3) using 0.40 g (0.52mmole) of the compound obtained in the above (1), there was obtained0.41 g (yield: 98%) of the 2′-O-acetyl compound.

(3) Following the same procedure as in Example 2 using 0.40 g (0.50mmole) of the compound obtained in the above (2), there was obtained0.40 g (yield: 90%) of the title compound.

Mass (IonSpray) m/z: 884.6 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.81(t, 3H, J=7.26 Hz, H15), 2.16 (s, 3H, NMe), 2.29 (s, 6H, NMe₂), 3.03 (s,3H, 6-OMe), 5.99 (m, 2H), 6.50 (m, 1H).

EXAMPLE 37

Synthesis of11-{2-[N-methyl-N-(2-methoxybenzyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

(1) Following the same procedure as in Example 3(1) using 0.40 ml (3.6mmoles) of 2-methoxybenzaldehyde in place of nicotinealdehyde and 2.35 g(3.04 mmoles) of the compound obtained in Example 1(1), there wasobtained the 11-{2-[N-methyl-N-(2-methoxylbenzyl)amino]ethyl}aminocompound, followed by the same procedure as in Example 3(2) to give 2.23g (yield: 85%) of the 3-hydroxyl compound.

(2) Following the same procedure as in Example 1(3) using 2.00 g (2.3mmoles) of the compound obtained in the above (1), there was obtained2.05 g (yield: 98%) of the 2′-O-acetyl compound.

(3) Following the same procedure as in Example 2 using 1.16 g (1.3mmoles) of the compound obtained in the above (2), there was obtained0.61 g (yield: 52%) of the title compound.

Mass (IonSpray) m/z: 911.6 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.73(t, 3H, J=7.26 Hz, H15), 2.25 (s, 3H, NMe), 2.29 (s, 6H, NMe₂), 3.00 (s,3H, 6-OMe), 3.62 (d, 1H, J=11.3 Hz), 3.69 (d, 1H, J=11.3 Hz), 3.80 (s,3H, Ph-OMe), 6.82 (m, 1H), 6.90 (m, 1H), 7.16 (m, 1H), 7.42 (m, 1H).

EXAMPLE 38

Synthesis of11-{2-[N-methyl-N-(4-fluorobenzyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

(1) A solution of 100 g (120 mmoles) of the compound obtained in Example1(1) in 150 ml of 1N aqueous hydrochloric acid solution was stirred at70° C. for an hour. The mixture was cooled to room temperature andextracted with chloroform. The aqueous layer was made basic with 2Naqueous sodium hydroxide solution and extracted with chloroform. Theorganic layer was washed with a saturated aqueous sodium chloridesolution and dried over anhydrous magnesium sulfate, followed byevaporation of the solvent. The residue was crystallized from ether togive 49 g (yield: 63%) of the 3-hydroxyl compound.

(2) To a solution of 44.5 g (67.7 mmoles) of the compound obtained inthe above (1) in 400 ml of methylene chloride were added 100 ml ofwater, 28.0 g (339 mmoles) of sodium bicarbonate and 24.0 ml (169mmoles) of benzylchloroformate, followed by reaction at room temperaturefor an hour. The reaction mixture was extracted with chloroform, and theorganic layer was washed with a saturated aqueous sodium chloridesolution, and dried over anhydrous magnesium sulfate, followed byevaporation of the solvent under reduced pressure to give theN,O-bis(benzyloxycarbonyl) compound. To a solution of the compound in500 ml of methylene chloride were successively added 23.4 g (135 mmoles)of 2-pyridylacetic acid hydrochloride, 25.9 g (135 mmoles) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.82 g(6.7 mmoles) of 4-dimethylaminopyridine under ice-cooling, followed bystirring at room temperature for 2 hours. The reaction solution waswashed with water and a saturated aqueous sodium chloride solution, andthe organic layer was dried over anhydrous magnesium sulfate, followedby evaporation of the solvent under reduced pressure. The residue waspurified by silica gel column chromatography(acetone:hexane:triethylamine=6:10:0.3) to give 50.0 g (yield: 71%) ofthe 3-O-(2-pyridyl)acetyl compound.

(3) To a solution of 50.0 g of the compound obtained in the above (2) inmethanol was added 10 g of 5% palladium-carbon, followed by stirringunder a hydrogen stream for 4 hours. After the reaction, thepalladium-carbon was removed by filtration, and the filtrate wasconcentrated to give the crude product, which was then recrystallizedfrom isopropyl ether to give 35.5 g (yield: 95%) of11-(2-aminoethyl)amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate.

Mass (IonSpray) m/z: 777.5 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.82(t, 3H, J=7.26 Hz, H15), 2.29 (s, 3H, NMe₂), 3.03 (s, 3H, 6-OMe), 5.06(1H, d, J=11.2 Hz, H3), 7.22 (m, 2H), 7.37 (m, 1H), 7.69 (m, 1H), 8.57(m, 1H).

(4) To a solution of 1.00 g (1.29 mmoles) of the compound obtained inthe above (3) in 10 ml of methanol were added 0.15 ml (1.42 mmoles) of4-fluorobenzaldehyde and 0.3 ml (5.0 mmoles) of acetic acid, then 0.55 g(2.58 mmoles) of sodium triacetoxyborohydride under ice-cooling. Thetemperature was turned to room temperature, followed by stirring for anhour. Then, 0.20 ml of 37% aqueous formaldehyde solution and 0.55 g(2.58 mmoles) of sodium triacetoxyborohydride were added to the mixture,and the temperature was turn to room temperature, followed by stirringfor 4 hours. The mixture was made basic with 4N sodium hydroxide andextracted with chloroform. The organic layer was dried over anhydrousmagnesium sulfate, followed by evaporation of the solvent under reducedpressure. The residue was purified by silica gel column chromatography(chloroform:methanol:aqueous ammonia=20:1:0.1) to give 0.38 g (yield:33%) of the title compound.

Mass (IonSpray) m/z: 899.5 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.72(t, 3H, J=7.26 Hz, H15), 2.17 (s, 3H, NMe), 2.29 (s, 6H, NMe₂), 3.03 (s,3H, 6-OMe), 6.94 (m, 2H), 7.27 (m, 2H).

EXAMPLE 39

Synthesis of11-{2-[N-ethyl-N-(3-pyridylmethyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Carrying out the same reaction as in Example 3(1) using 0.66 g(0.85mmole) of the compound obtained in Example 38(3) and 0.16 ml(2.58mmoles) of 90% acetaldehyde in place of 37% aqueous formaldehydesolution, there was obtained 0.64 g of the title compound.

MS (SIMS); m/z 896 [M+H]⁺; ¹H-NMR (500 MHz, CDCl₃) δ(ppm): 2.29 (6H, s,N(CH₃ )₂), 2.98 (3H, s, 6-OCH₃), 5.05 (1H, d, J=11.0 Hz, 3-H), 5.09 (1H,dd, J=11.0, 2.4 Hz, 13-H). ¹³C-NMR (125 MHz, CDCl₃) δ(ppm): 40.3 (Q,N(CH₃)₂), 50.1 (Q, 6-OCH₃), 174.3 (S, C1), 215.7 (S, C9).

EXAMPLE 40

Synthesis of11-{2-[N-methyl-N-(2-hydroxybenzyl)amino]ethyl}amino-11-deoxy-³-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Following the same procedure as in Example 38(4) using 0.21 ml (1.94mmoles) of 2-hydroxybenzaldehyde in place of 4-fluorobenzaldehyde, therewas obtained 1.05 g (yield: 67%) of the title compound.

Mass (IonSpray) m/z: 897.5 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.79(t, 3H, J=7.08 Hz, H15), 2.29 (s, 6H, NMe₂), 2.33 (s, 3H, NMe), 3.01 (s,3H, 6-OMe), 6.78 (m, 2H), 6.95 (m, 1H), 7.13 (m, 1H).

EXAMPLE 41

Synthesis of11-{2-[N-methyl-N-(2-fluorobenzyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Following the same procedure as in Example 38(4) using 0.15 ml (1.42mmoles) of 2-fluorobenzaldeyde in place of 4-fluorobenzaldehyde, therewas obtained 0.50 g (yield: 43%) of the title compound.

Mass (IonSpray) m/z: 899.5 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.73(t, 3H, J=7.26 Hz, H15), 2.24 (s, 3H, NMe), 2.29 (s, 6H, NMe₂), 3.03 (s,3H, 6-OMe), 3.62 (d, 1H, J=13.6 Hz), 3.79 (d, 1H, J=13.6 Hz), 6.97 (m,1H), 7.06 (m, 1H), 7.16 (m, 1H), 7.42 (m, 1H).

EXAMPLE 42

Synthesis of11-{2-[N-methyl-N-(2-nitrobenzyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Following the same procedure as in Example 38(4) using 0.22 g (1.42mmoles) of 2-nitrobenzaldehyde in place of 4-fluorobenzaldehyde, therewas obtained 0.25 g (yield: 21%) of the title compound.

Mass (IonSpray) m/z: 926 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.67(t, 3H, J=7.26 Hz, H15), 2.24 (s, 3H, NMe), 2.30 (s, 6H, NMe₂), 3.00 (s,3H, 6-OMe), 7.34 (m, 1H), 7.54 (m, 1H), 7.84 (m, 1H).

EXAMPLE 43

Synthesis of11-{2-[N-methyl-N-(2-aminobenzyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Following the same procedure as in Example 26 using 0.21 g (0.23 mmole)of the compound obtained in Example 42, there was obtained 0.15 g(yield: 73%) of the title compound.

Mass (IonSpray) m/z; 896 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.80(t, 3H, J=7.26 Hz, H15), 2.17 (s, 3H, NMe), 2.29 (s, 6H, NMe₂), 3.03 (s,3H, 6-OMe), 3.59 (m, 2H), 4.72 (brs, 2H), 6.60 (m, 2H), 6.96 (m, 1H),7.04 (m, 1H).

EXAMPLE 44

Synthesis of11-{2-[N-methyl-N-(2-cyanobenzyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Following the same procedure as in Example 38(4) using 0.20 g (1.54mmoles) of 2-cyanobenzaldehyde in place of 4-fluorobenzaldehyde, therewas obtained 0.25 g (yield: 22%) of the title compound.

Mass (IonSpray) m/z: 906 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.70(t, 3H, J=7.26 Hz, H15), 2.26 (s, 3H, NMe), 2.30 (s, 6H, NMe₂), 3.00 (s,3H, 6-OMe), 7.29 (m, 1H), 7.52 (m, 1H), 7.58 (m, 1H), 7.66 (m, 1H).

EXAMPLE 45

Synthesis of11-{2-[N-methyl-N-(2-hydroxy-4-methoxybenzyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Following the same procedure as in Example 38(4) using 0.32 g (2.14mmoles) of 2-hydroxy-4-methoxybenzaldehyde in place of4-fluorobenzaldehyde, there was obtained 0.73 g (yield: 44%) of thetitle compound.

Mass (IonSpray) m/z: 927 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.80(t, 3H, J=7.26 Hz, H15), 2.29 (s, 6H, NMe₂), 2.32 (s, 3H, NMe), 3.01 (s,3H, 6-OMe), 3.75 (s, 3H, Ph-OMe), 6.31 (dd, 1H, J=8.32, 2.48 Hz), 6.39(d, 1H, J=2.48 Hz), 6.83 (d, 1H, J=8.32 Hz).

EXAMPLE 46

Synthesis of11-{2-[N-methyl-N-(2-benzofuranylmethyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Following the same procedure as in Example 38(4) using 0.49 g (3.35mmoles) of benzofuran-2-carboxaldehyde in place of 4-fluorobenzaldehyde,there was obtained 0.77 g (yield: 33%) of the title compound.

Mass (IonSpray) m/z: 921 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.77(t, 3H, J=7.26 Hz, H15), 2.30 (s, 6H, NMe₂), 2.39 (s, 3H, NMe), 3.00 (s,3H, 6-OMe), 6.48 (m, 1H), 7.14˜7.24 (m, 3H), 7.42 (m, 1H), 7.50 (m, 1H).

EXAMPLE 47

Synthesis of11-{2-[N-methyl-N-(4-acetamidobenzyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Following the same procedure as in Example 38(4) using 0.55 g (3.35mmoles) of 4-acetamidobenzaldehyde in place of 4-fluorobenzaldehyde,there was obtained 0.96 g (yield: 40%) of the title compound.

Mass (IonSpray) m/z: 938 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.76(t, 3H, J=7.26 Hz, H15), 2.03 (s, 3H, NAc), 2.24 (s, 3H, NMe), 2.29 (s,6H, NMe₂), 2.74 (s, 3H, 6-OMe), 7.24 (m, 3H), 7.32 (m, 3H), 7.64 (brs,1H, NHAc).

EXAMPLE 48

Synthesis of11-{2-[N-methyl-N-(2,3-methylenedioxybenzyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Following the same procedure as in Example 38(4) using 0.16 ml (1.42mmoles) of 2,3-methylenedioxybenzaldehyde in place of4-fluorobenzaldehyde, there was obtained 0.63 g (yield: 54%) of thetitle compound.

Mass (IonSpray) m/z: 911.5 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.74(t, 3H, J=7.26 Hz, H15), 2.29 (s, 6H, NMe₂), 3.01 (s, 3H, 6-OMe), 5.92(m, 2H), 6.69 (dd, 1H, J=7.61, 1.96 Hz), 6.73 (t, 1H, J=7.61 Hz), 6.80(dd, 1H, J=7.61, 1.96 Hz).

EXAMPLE 49

Synthesis of11-{2-[N-methyl-N-(4-dimethylaminobenzyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Following the same procedure as in Example 38(4) using 0.13 g (1.02mmoles) of 4-dimethylaminoenzaldehyde in place of 4-fluorobenzaldehyde,there was obtained 0.56 g (yield: 67%) of the title compound.

Mass (IonSpray) m/z: 924.5 [M+H]⁺.

EXAMPLE 50

Synthesis of11-{2-[N-(2-hydroxy-4-methoxybenzyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

To a solution of 1.38 g (1.78 mmoles) of the compound obtained inExample 38(3) in 20 ml of methanol were added 0.32 9 (2.14 mmoles) of2-hydroxy-4-methoxybenzaldehyde and 0.40 ml (6.67 mmoles) of aceticacid, then 0.75 g (3.55 mmoles) of sodium triacetoxyborohydride underice-cooling. The temperature was turned to room temperature, followed bystirring for 4 hours. The mixture was made basic with 4N sodiumhydroxide and extracted with diethyl ether. The organic layer was driedover anhydrous potassium carbonate, followed by evaporation of thesolvent under reduced pressure. The residue was purified by silica gelcolumn chromatography (chloroform:methanol:aqueous ammonia=20:1:0.1) togive 0.98 g (yield: 60%) of the title compound.

Mass (IonSpray) m/z: 913 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.82(t, 3H, J=7.26 Hz, H15), 2.29 (s, 6H, NMe₂), 3.02 (s, 3H, 6-OMe), 3.75(s, 3H, Ph-OMe), 6.31 (dd, 1H, J=8.32, 2.48 Hz), 6.40 (d, 1H, J=2.48Hz), 6.87 (d, 1H, J=8.32 Hz).

EXAMPLE 51

Synthesis of11-{2-[N-(4-quinolylmethyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Following the same procedure as in Example 50 using 0.24 g (1.55 mmoles)of 4-quinolinecarboxaldehyde in place of2-hydroxy-4-methoxybenzaldehyde, there was obtained 0.42 g (yield: 36%)of the title compound.

Mass (IonSpray) m/z: 918.5 [M+H]⁺;

EXAMPLE 52

Synthesis of11-{2-[N-(3H-1-oxaisoindolyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Following the same procedure as in Example 50 using 0.55 g (3.35 imoles)of 2-methoxycarbonylbenzaldehyde in place of2-hydroxy-4-methoxybenzaldehyde, there was obtained 1.01 g (yield: 44%)of the title compound.

Mass (IonSpray) m/z: 893 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.83(t, 3H, J=7.26 Hz, H15), 2.29 (s, 6H, NMe₂), 3.12 (s, 3H, 6-OMe), 4.45(d, 1H, J=16.6 Hz), 4.60 (d, 1H, J=16.6 Hz), 7.41 (m, 2H), 7.50 (m, 1H),7.82 (m, 1H).

EXAMPLE 53

Synthesis of11-[2-(N-nicotinoyl)aminoethyl]amino-11-deoxy-3-O-(2-pyridyl)-acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12 cyclic carbamate

To a solution of 0.50 g (0.64 mmole) of the compound obtained in Example38(3) in 10 ml of methylene chloride were added 0.14 g (0.77 mmole) ofnicotinoyl chloride hydrochloride and 0.12 ml (1.54 mmoles) of pyridine,followed by stirring at room temperature for an hour. The reactionsolution was made basic with 4N sodium hydroxide and extracted withchloroform. The organic layer was dried over anhydrous potassiumcarbonate, followed by evaporation of the solvent under reducedpressure. The residue was purified by silica gel column chromatography(chloroform:methanol:aqueous ammonia=20:1:0.1) to give 0.33 g (yield:59%) of the title compound.

Mass (IonSpray) m/z: 882.5 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.65(t, 3H, J=7.26 Hz, H15), 2.29 (s, 6H, NMe₂), 3.08 (s, 3H, 6-OMe), 7.32(dd, 1H, J=7.96, 4.96 Hz), 7.80 (brt, 1H, J=4.78 Hz), 8.16 (ddd, 1H,J=7.96, 1.59, 1.59 Hz), 8.67 (dd, 1H, J=4.96, 1.59 Hz), 9.03 (d, 1H,J=1.59 Hz).

EXAMPLE 54

Synthesis of11-[2-(N-benzoyl)aminoethyl]amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Following the same procedure as in Example 53 using benzoyl chloride inplace of nicotinoyl chloride hydrochloride, there was obtained 0.35 g(yield: 62%) of the title compound.

Mass (IonSpray) m/z: 881.5 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.61(t, 3H, J=7.26 Hz, H15), 2.29 (s, 6H, NMe₂), 3.09 (s, 3H, 6-OMe),7.32-7.46 (m, 4H), 7.84 (m, 2H).

EXAMPLE 55

Synthesis of11-{2-[N-(1-naphthoyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)-acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Following the same procedure as in Example 53 using 1-naphthoyl chloridein place of nicotinoyl chloride hydrochloride, there was obtained 0.40 g(yield: 67%) of the title compound.

Mass (IonSpray) m/z: 931.6 [M+H]⁺.

EXAMPLE 56

Synthesis of11-{2-[N-(4-biphenylcarbonyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Following the same procedure as in Example 53 using 4-biphenylcarbonylchloride in place of nicotinoyl chloride hydrochloride, there wasobtained 0.38 g (yield: 62%) of the title compound.

Mass (IonSpray) m/z: 957.6 [M+H]⁺.

EXAMPLE 57

Synthesis of11-{2-[N-(3-quinolinoyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)-acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

To a solution of 0.50 g (0.64 mmole) of the compound obtained in Example38(3) in 10 ml of methylene chloride were added 0.13 g (0.77 mmole) of3-quinolylcarboxylic acid, 0.15 g (0.77 nmole) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.05 g(0.41 mmole) of 4-dimethylaminopyridine, followed by stirring at roomtemperature for an hour. The reaction solution was washed with water anda saturated aqueous sodium chloride solution, and the organic layer wasdried over anhydrous magnesium sulfate, followed by evaporation of thesolvent under reduced pressure. The residue was purified by silica gelcolumn chromatography (chloroform:methanol:aqueous ammonia=20:1:0.1) togive 0.26 g (yield: 44%) of the title compound.

Mass (IonSpray) m/z: 932.6 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.57(t, 3H, J=7.26 Hz, H15), 2.29 (s, 6H, NMe₂), 3.11 (s, 3H, 6-OMe), 7.56(m, 1H), 7.77 (m, 1H), 7.84 (brd, 1H, J=7.8 Hz), 7.92 (brt, 1H, J=5.0Hz), 8.15 (d, 1H, J=8.3 Hz), 8.62 (d, 1H, J=2.0 Hz), 9.36 (d, 1H, J=2.3Hz).

EXAMPLE 58

Synthesis of11-{2-[N-(2-nitrobenzylidene)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

To a solution of 2.00 g (2.58 mmoles) of the compound obtained inExample 38(3) in 30 ml of methanol were added 0.44 g (2.84 mmoles) of2-nitrobenzaldehyde and 0.6 ml (10.0 mmoles) of acetic acid, followed bystirring for an hour. The reaction solution was made basic with 4Nsodium hydroxide and extracted with chloroform. The organic layer wasdried over anhydrous magnesium sulfate, followed by evaporation of thesolvent under reduced pressure. The residue was purified by silica gelcolumn chromatography (chloroform:methanol:aqueous ammonia=20:1:0.1) togive 1.32 g (yield: 56%3 of the title compound.

Mass (IonSpray) m/z: 910.5 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.50(t, 3H, J=7.26 Hz, H15), 2.30 (s, 6H, NMe₂), 3.08 (s, 3H, 6-OMe), 8.83(s, 1H, —N═CH).

EXAMPLE 59

Synthesis of11-{2-[N-(2-cyanobenzylidene)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Following the same procedure as in Example 58 using 0.20 g (1.54 mmoles)of 2-cyanobenzaldehyde in place of 2-nitrobenzaldehyde, there wasobtained 0.53 g (yield: 47%) of the title compound.

Mass (IonSpray) m/z: 890 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.61(t, 3H, J=7.25 Hz, H15), 2.29 (s, 6H, NMe₂), 3.08 (s, 3H, 6-OMe), 8.80(s, 1H, —N═CH).

EXAMPLE 60

Synthesis of11-{2-[N-(2-imidazolylmethylene)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Following the same procedure as in Example 58 using 0.32 g (3.35 mmoles)of imidazole-2-carboxaldehyde in place of 2-nitrobenzaldehyde, there wasobtained 0.60 g (yield: 27%) of the title compound.

Mass (IonSpray) m/z: 855 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.66(t, 3H, J=7.43 Hz, H15), 2.29 (s, 6H, NMe₂), 2.89 (s, 3H, 6-OMe), 8.24(s, 1H, —N═CH).

EXAMPLE 61

Synthesis of11-{2-[N-(2-trifluoromethylbenzylidene)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Following the same procedure as in Example 58 using 0.20 ml (1.55mmoles) of 2-trifluoromethylbenzaldehyde in place of2-nitrobenzaldehyde, there was obtained 0.78 g (yield: 65%) of the titlecompound.

Mass (IonSpray) m/z: 933.5 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.55(t, 3H, J=7.26 Hz, H15), 2.29 (s, 6H, NMe₂), 3.08 (s, 3H, 6-OMe), 8.78(s, 1H, —N═CH).

EXAMPLE 62

Synthesis of11-{2-[N-acetyl-N-(3-pyridylmethyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

(1) To a solution of 10.3 g (12.0 mmoles) of the compound obtained inExample 1(1) in 100 ml of methanol were added 1.1 ml (12.0 mmoles) ofnicotinealdehyde and 2.0 ml (35.0 mmoles) of acetic acid, then 0.9 g(14.3 mmoles) of sodium cyanoborohydride under ice-cooling. The mixturewas stirred at room temperature for 3 hours. After the reaction, themixture was diluted with ethyl acetate, and successively washed with anaqueous sodium hydroxide solution and a saturated aqueous sodiumchloride solution. The organic layer was dried over anhydrous magnesiumsulfate, followed by evaporation of the solvent under reduced pressureto give 10.5 g of4″-O-acetyl-11-{2-[N-(3-pyridylmethyl)amino]ethyl}amino-11-deoxy-6-O-methylerythromycinA 11,12-cyclic carbamate.

Mass (FAB) m/z: 949 [M+H]⁺.

(2) Following the same procedure as in Example 3(2) using 8.3 g of thecompound obtained in the above (1), there was obtained 6.7 g of the3-hydroxyl compound.

(3) Following the same procedure as in Example 1(3) for acetylationusing 2.20 g of the compound obtained in the above (2) and 0.83 ml (8.8mmoles) of acetic anhydride, there was obtained 2.47 g of2′-O-acetyl-11-{2-[N-acetyl-N-(3-pyridylmethyl)-amino]ethyl}amino-11-deoxy-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate.

Mass (SIMS) m/z: 833 [M+H]⁺.

(4) Following the same procedure as in Example 2 using 0.81 g (0.97mmole) of the compound obtained in the above (3), there was obtained0.37 g (yield: 42%) of the title compound.

Mass (SIMS) m/z: 910 [M+H]⁺; ¹H-NMR (500 MHz, DMSO-d₆) δ(ppm): 2.02 (s,3H, —COCH₃), 2.22 (s, 6H, N(CH₃)₂), 2.71 (s, 3H, 6-OMe).

EXAMPLE 63

Synthesis of11-{2-[N-acetyl-N-(3-pyridylmethyl)amino]ethyl}amino-11-deoxy-3-O-(3-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Following the same procedure as in Example 1(4) using 0.81 g (0.97mmole) of the compound obtained in Example 62(3), there was obtained0.34 g (yield: 39%) of the title compound.

Mass (SIMS) m/z: 910 [M+H]⁺; ¹H-NMR (200 MHz, DMSO-d₆) δ(ppm): 2.03 (s,3H, —COCH₃), 2.23 (s, 6H, N(CH₃)₂), 2.73 (s, 3H, 6-OMe).

EXAMPLE 64

Synthesis of11-{2-[N-tert-butoxycarbonyl-N-(3-pyridylmethyl)amino]ethyl}amino-11-deoxy-3-O-(3-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

(1) To a solution of 2.31 g (3.1 mmoles) of the compound obtained inExample 62(2) in 25 ml of acetone was added 2.0 g (9.2 mmoles) ofdi-tert-butyldicarbonate, followed by stirring at room temperature for 2hours. After the reaction, the mixture was diluted with ethyl acetate,and successively washed with a saturated aqueous sodium bicarbonatesolution and a saturated aqueous sodium chloride solution. The organiclayer was dried over anhydrous magnesium sulfate, followed byevaporation of the solvent under reduced pressure to give 3.57 g of11-{2-[N-tert-butoxycarbonyl-N-(3-pyridylmethyl)amino]-ethyl}amino-2′-O-(tert-butoxycarbonyl)-11-deoxy-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate.

(2) Following the same procedure as in Example 1(4) using 1.21 g (1.27mmoles) of the compound obtained in the above (1), there was obtained0.73 g of the 3-pyridylacetyl compound. The compound was dissolved in 15ml of methanol, and stirred overnight. After evaporation of the solvent,purification by silica gel column chromatography(chloroform:methanol:aqueous ammonia=15:1:0.1) gave 0.38 g (yield: 31%)of the title compound.

Mass (SIMS) m/z: 968 [M+H]⁺; ¹H-NMR (500 MHz, DMSO-d_(6, 60)° C.)δ(ppm): 1.39 (s, 9H, t-Bu), 2.24 (s, 6H, N(CH₃)₂), 2.77 (s, 3H, 6-OMe),3.83 and 3.95 (each d, each 1H, J_(gem)=16.5 Hz, —COCH_(2[)3-Pyr.]),4.41 and 4.53 (each d, each 1H, J_(gem)=15.9 Hz, —NCH₂[3-Pyr.]), 4.89(d, 1H, J=11.0 Hz, H-3), 4.89 (d, 1H, J=11.0 Hz, H-3) ¹³C-NMR (125 MHz,DMSO-d_(6, 60)° C.) δ(ppm): 27.7 (t-Bu), 37.1 (—COCH₂[3-Pyr.]), 40.0(N(CH₃)₂), 49.7 (—NCH₂[3-Pyr.]), 49.1 (6-OMe), 102.6 (C1′), 156.0(11,12-carbamate), 170.5 (—COCH₂[3-Pyr.]), 173.8 (C1), 215.2 (C9).

EXAMPLE 65

Synthesis of11-{2-[N-(3-pyridylmethyl)amino]ethyl}amino-11-deoxy-3-O-(3-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

To a solution of 0.17 g (0.18 mmole) of the compound obtained in Example64 in 3 ml of methylene chloride was added 0.5 ml of trifluoroaceticacid under ice-cooling, followed by stirring for 3 hours. After thereaction, an aqueous sodium hydroxide solution was added to the mixture,followed by extraction with chloroform. The organic layer was dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (chloroform:methanol: aqueous ammonia=10:1:0.1) to give0.14 g (yield: 92%) of the title compound.

Mass (SIMS) m/z: 868 [M+H]⁺; ¹H-NMR (500 MHz, CDCl₃) δ(ppm): 2.28 (s,6H, N(CH₃)₂), 3.03 (s, 3H, 6-OMe), 5.03 (d, 1H, J=11.6 Hz, H-3), 5.32(dd, 1H, J=11.6, 2.4 Hz, H-13) ¹³C-NMR (125 MHz, CDCl₃) δ(ppm): 40.3(N(CH₃)₂), 50.1 (6-OMe), 103.8 (C1′), 158.0 (11,12-carbamate), 170.4(—COCH₂[3-Pyr.]), 174.1 (C1), 215.9 (C9)

EXAMPLE 66

Synthesis of11-{2-[N-(3-pyridylmethyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Following the same procedures as in Examples 2 and 65 using 2.15 g (2.3mmoles) of the compound obtained in Example 64(1), there was obtained0.10 g of the title compound.

Mass (FAB) m/z: 868 [M+H]⁺; ¹H-NMR (500 MHz, CDCl₃) δ(ppm): 2.29 (s, 6H,N(CH₃ )₂), 3.02 (s, 3H, 6-OMe), 3.81 and 3.88 (each d, each 1H,J_(gem)=13.4 Hz, —NCH₂ [3-Pyr.]), 3.92 and 3.96 (each d, each 1 E,J_(gem)=15.9 Hz, —COCH₂ [2-Pyr.]), 4.07 (d, 1H, J=6.7 Hz, H-1′), 5.05(d, 1H, J=11.0 Hz, H-3), 5.32 (dd, 1H, J=11.0, 2.4 Hz, H-13) ¹³C-NMR(125 MHz, CDCl₃) δ(ppm): 40.3 (N(CH₃)₂), 50.1 (6-OMe), 103.5 (C1′),158.0 (11,12-carbamate), 170.5 (—COCH₂[2-Pyr.]), 174.3 (C1), 216.0 (C9)

EXAMPLE 67

Synthesis of11-{2-[N-(2-pyridyl)acetyl-N-(3-pyridylmethyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Following the same procedure as in Example 2 using 0.64 g (0.85 mmole)of the compound obtained in Example 62(2), 0.78 g (4.50 mmoles) of2-pyridylacetic acid hydrochloride, 0.86 9 (4.5 mmoles) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.13 g(1.1 mmoles) of 4-dimethylaminopyridine, there was obtained 0.25 g(yield: 30%) of the title compound.

Mass (SIMS) m/z: 987 [M+H]⁺; ¹H-NMR (500 MHz, CDCl₃) δ(ppm): 2.29 (s,6H, N(CH₃ )₂), 2.84 (s, 3H, 6-OMe) ¹³C-NMR (125 MHz, CDCl₃) δ(ppm): 40.3(N(CH₃)₂), 103.7 (C1′), 216.1 (C9)

EXAMPLE 68

Synthesis of11-{2-[N-(2-pyridylacetyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Following the same procedure as in Example 2 for 2-pyridylacetylation,using 1.04 g (1.6 mmoles) of the compound obtained in Example 38(1),0.83 g (4.8 mmoles) of 2-pyridylacetic acid hydrochloride, 0.91 g (4.7mmoles) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlorideand 0.10 g (0.8 mmole) of 4-dimethylaminopyridine, there was obtained0.56 g (yield: 39%) of the title compound.

Mass (SIMS) m/z: 896 [M+H]⁺; ¹H-NMR (500 MHz, CDCl₃) δ(ppm): 2.29 (s,6H, N(CH₃ )₂), 3.04 (s, 3H, 6-OMe), 3.92 and 3.96 (each d, each 1H,J_(gem)=15.9 Hz, —COCH₂ [2-Pyr.]), 4.07 (d, 1H, J=7.3 Hz, H-1′), 5.05(d, 1H, J=11.0 Hz, H-3), 5.09 (dd, 1H, J=11.0, 2.4 Hz, H-13). ¹³C-NMR(125 MHz, CDCl₃) δ(ppm): 40.3 (N(CH₃)₂), 50.3 (6-OMe), 103.6 (C1′),157.6 (11,12-carbamate), 169.6 and 170.4 (each —COCH₂[2-Pyr.]), 174.7(C1), 215.5 (C9).

EXAMPLE 69

Synthesis of11-{2-[N-methyl-N-(3-pyridylmethyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminylerythronolideA 11,12-cyclic carbamate

(1) 20.3 g (23.6 mmoles) of10,11-anhydro-2′,4″-bis-O-trimethylsilylerythromycin A was dissolved in400 ml of 0.5N aqueous hydrochloric acid solution, and stirred at roomtemperature for 7 hours. After the reaction, the mixture was made basicwith an aqueous sodium hydroxide solution and extracted with chloroform.The organic layer was dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue wasrecrystallized from 2-propanol/n-hexane to give 7.3 g (yield: 55%) of10,11-anhydro-5-O-desosaminylerythronolide A as the first crystals.

Mass (SIMS) m/z: 558 [M+H]⁺; ¹H-NMR (500 MHz, CDCl₃) δ(ppm): 2.06 (d,3H, J=1.5 Hz, 10Me), 2.28 (s, 6H, N(CH₃ )₂), 4.43 (d, 1H, J=7.4 Hz,H-1′), 4.99 (dd, 1H, J=11.0, 1.8 Hz, H-13), 6.44 (d, 1H, J=1.5 Hz, H-11)¹³C-NMR (125 MHz, CDCl₃) δ(ppm): 12.8 (10Me), 40.2 (N(CH₃)₂), 106.2(C1′), 139.6 (C10), 141.1 (C11), 177.0(C1), 207.9(C9)

(2) Following the same procedure as in Example 1(3) using 9.28 g (16.6mmoles) of the compound obtained in the above (1), there was obtained9.70 g of the 2′-O-acetyl compound.

(3) To a solution of 9.70 g of the compound obtained in the above (2) in200 ml of methylene chloride were successively added 2.8 g (33.3 mmoles)of sodium bicarbonate, 4.3 g (25 mmoles) of 2-pyridylacetic acidhydrochloride, 4.8 g (25 mmoles) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 3.05 g(25 mmoles) of 4-dimethylaminopyridine under icecooling, followed bystirring at room temperature for 1.5 hours. After the reaction, asaturated aqueous sodium bicarbonate solution was added to the mixture,followed by extraction with chloroform. The organic layer was dried overanhydrous magnesium sulfate under reduced pressure, and purification bysilica gel column chromatography(acetone:n-hexane:triethylamine=10:10:0.2) gave 8.11 g (yield: 68%) of10,11-anhydro-2′-O-acetyl-3-O-(2-pyridyl)acetyl-5-O-desosaminylerythronolideA.

Mass (SIMS) m/z: 719 [M+H]⁺; ¹H-NMR (500 MHz, CDCl₃) δ(ppm): 2.02 (s,3H, 10Me), 2.10 (s, 3H, —COCH₃ ), 2.27 (s, 6H, N(CH₃ )₂), 3.88 and 3.94(each d, each 1H, J_(gem)=15.9 Hz, —COCH₂ [2-Pyr.]), 4.27 (d, 1H, J=7.9Hz, H-1′), 5.24 (dd, 1H, J=11.0, 1.8 Hz, H-13), 5.31 (d, 1H, J=7.3 Hz,H-3), 6.37 (s, 1H, H-11) ¹³C-NMR (125 MHz, CDCl₃) δ(ppm): 40.7(N(CH₃)₂), 101.3 (C1′), 140.1 (C11), 140.7 (C10), 169.8 (—COCH₃), 170.3(—COCH₂[2-Pyr.]), 173.2(C1), 206.5(C9)

(4) 1.34 g (1.87 mmoles) of the compound obtained in the above (3) wasdissolved in 18 ml of tetrahydrofuran and 12 ml ofN,N-dimethylformamide, and 0.22 g (5.5 mmoles) of sodium hydride wasadded thereto under ice-cooling, followed by stirring under ice-coolingfor 2 hours. After the reaction, the mixture was diluted with ethylacetate, and successively washed with distilled water and a saturatedaqueous sodium chloride solution. The organic layer was dried overanhydrous magnesium sulfate, and evaporation of the solvent underreduced pressure gave 1.42 g of the 12-O-imidazolylcarbonyl compound.The compound was dissolved in 30 ml of acetonitrile, and 3.09 g (18.7mmoles) of 2-[N-methyl-N-(3-pyridylmethyl)amino]ethylamine was addedthereto, followed by stirring at room temperature for 2 days. After thereaction, the solvent was evaporated, and the residue was dissolved in80 ml of methanol and stirred overnight. After the reaction, the solventwas evaporated, and the residue was purified by silica gel columnchromatography (chloroform:methanol:aqueous ammonia=20:1:0.1) to give0.46 g (yield: 28%) of the title compound.

Mass (FAB) m/z: 868 [M+H]⁺; ¹H-NMR (500 MHz, DMSO-d₆) δ(ppm): 2.05 (s,3H, NCH₃ ), 2.24 (s, 6H, N(CH₃ )₂), 3.38 and 3.59 (each d, each 1H,J_(gem)=13.4 Hz, —NCH₂ [3-Pyr.]), 3.84 (s, 1H, H-11), 3.99 (d, 1H, J=7.0Hz, H-1′), 3.93 and 4.06 (each d, each 1H, J_(gem)=16.2 Hz, —COCH₂[2-Pyr.]), 5.09 (dd, 1H, J=8.2, 4.0 Hz, H-13), 5.12 (d, 1H, J=11.0 Hz,H-3) ¹³C-NMR (125 MHz, DMSO-d₆) δ(ppm): 40.4 (N(CH₃)₂), 41.4 (NCH₃),58.3 (—NCH₂[3-Pyr.]), 102.4 (C1′), 155.4 (11,12-carbamate), 170.3(—COCH₂[2-Pyr.]), 173.3 (C1), 215.3 (C9)

EXAMPLE 70

Synthesis of11-{2-[N-methyl-N-(3-pyridylmethyl)amino]ethyl}amino-11-deoxy-3-O-(4-methoxyphenylamino)carbonyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

(1) To a solution of 11.0 g (16.7 mmoles) of the compound obtained inExample 38(1) in 150 ml of methylene chloride were successively added1.97 g (18.4 mmoles) of nicotinealdehyde and 7.08 g (33.4 mmoles) ofsodium triacetoxyborohydride at room temperature, followed by stirringfor an hour. Then, 2.7 ml (33.4 mmoles) of 37% aqueous formaldehydesolution and 3.54 g (16.7 mmoles) of sodium triacetoxyborohydride wereadded to the mixture, followed by stirring for 2.5 hours. The reactionsolution was diluted with chloroform and successively washed with anaqueous sodium hydroxide solution and a saturated aqueous sodiumchloride solution, and the organic layer was dried over anhydrousmagnesium sulfate. Evaporation of the solvent under reduced pressuregave 14.1 g of11-{2-[N-methyl-N-(3-pyridylmethyl)amino]ethyl}amino-11-deoxy-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate.

(2) Carrying out the same reaction as in Example 1(3) using 14.1 g ofthe compound obtained in the above (1), there was obtained 14.4 g of the2′-O-acetyl compound.

(3) To a solution of 0.50 g (0.62 mmole) of the compound obtained in theabove (2) in 15 ml of methylene chloride was added 0.50 ml (6.2 mmoles)of pyridine. 0.092 g (0.31 imole) of triphosgene was added thereto underice-cooling, followed by stirring for 1.5 hours. Then, 0.38 g (3.1mmoles) of p-anisidine was added to the mixture, followed by stirringfor further an hour. To the reaction solution was added water todecompose excess triphosgene, and the mixture was diluted withchloroform and successively washed with a saturated aqueous ammoniumchloride solution and a saturated aqueous sodium chloride solution. Theorganic layer was dried over anhydrous magnesium sulfate, the solventwas evaporated under reduced pressure, and the resulting residue wasdissolved in methanol, followed by heating under reflux for 3 hours.After allowing to stand for cooling, the solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography (acetone:hexane:triethylamine=10:10:0.2) to give 0.26 g(yield: 46%) of the title compound.

Mass (IonSpray) m/z: 912.5 [M+H]⁺; ¹H-NMR (500 MHz, CDCl₃) δ(ppm): 0.74(t, 3H, J=7.3 Hz, H-15), 2.17 (s, 6H, 3′-N(CH₃)₂), 2.20 (s, 3H, NCH₃),3.06(s, 3H, 6-OCH₃), 3.78 (s, 3H, ArOCH₃), 4.95 (d, 1H, J=11.3 Hz, H-3),5.23 (dd, 1H, J=11.0, 2.1 Hz, H-13), 6.98 (brs, 1H, NH) ¹³C-NMR (125MHz, CDCl₃) δ(ppm): 55.6 (ArOCH₃), 153.5 (3-carbamate)

EXAMPLE 71

Synthesis of11-{2-[N-methyl-N-(3-pyridylmethyl)amino]ethyl}amino-11-deoxy-3-O-(2-methoxyphenylamino)carbonyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Carrying out the same reaction as in Example 70(3) using 0.50 g (0.62mmole) of the compound obtained in Example 70(2) and 0.38 g (3.10mmoles) of o-anisidine, there was obtained 0.23 g (yield: 41%) of thetitle compound.

Mass (IonSpray) m/z: 912.5 [M+H]⁺; ¹H-NMR (500 MHz, CDCl₃) δ(ppm): 0.75(t, 3H, J=7.3 Hz, H-15), 2.15 (s, 6H, 3′-N(CH₃)₂), 2.20 (s, 3H, NCH₃),3.08 (s, 3H, 6-OCH₃), 3.89 (s, 3H, ArOCH₃), 4.99 (d, 1H, J=11.6 Hz,H-3), 5.25 (dd, 1H, J=11.0, 2.1 Hz, H-13), 7.39 (brs, 1H, NH) ¹³C-NMR(125 MHz, CDCl₃) 55.6 (ArOCH₃), 153.2 (3-carbamate)

EXAMPLE 72

Synthesis of11-{2-[N-methyl-N-(3-pyridylmethyl)amino]ethyl}amino-11-deoxy-3-O-(3-methoxyphenylamino)carbonyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Carrying out the same reaction as in Example 70(3) using 0.50 g (0.62mmole) of the compound obtained in Example 70(2) and 0.38 g (3.10mmoles) of m-anisidine, there was obtained 0.20 g (yield: 35%) of thetitle compound.

Mass (IonSpray) m/z: 912.5 [M+H]⁺; ¹H-NMR (500 MHz, CDCl₃) δ(ppm): 0.74(t, 3H, J=7.3 Hz, H-15), 2.17 (s, 6H, 3′-N(CH₃)₂), 2.20 (S, 3H, NCH₃),3.07 (s, 3H, 6-OCH₃), 3.79 (s, 3H, ArOCH₃), 4.97 (d, 1H, J=10.9 Hz,H-3), 5.24 (dd, 1H, J=11.0, 1.9 Hz, H-13), 8.13 (brs, 1H, NH) ¹³C-NMR(125 MHz, CDCl₃) δ(ppm): 55.2 (ArOCH₃), 153.4 (3-carbamate)

EXAMPLE 73

Synthesis of11-{2-[N-methyl-N-(3-pyridylmethyl)amino]ethyl}amino-11-deoxy-3-O-(phenylamino)carbonyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Carrying out the same reaction as in Example 70(3) using 0.50 g (0.62mmole) of the compound obtained in Example 70(2) and 0.29 g (3.10mmoles) of aniline, there was obtained 0.22 g (yield: 40%) of the titlecompound.

Mass (IonSpray) m/z: 882.4 [M+H]⁺; ¹H-NMR (500 MHz, CDCl₃) δ(ppm): 0.74(t, 3H, J=7.3 Hz, H-15), 2.15 (s, 6H, 3′-N(CH₃)₂), 2.20 (s, 3H, NCH₃),3.07 (s, 3H, 6-OCH₃), 4.97 (d, 1H, J=10.9 Hz, H-3), 5.23 (dd, 1H,J=11.0, 2.5 Hz, H-13), 7.05 (t, 1H, J=7.5 Hz, Ar-H), 7.30 (t, 2H, J=7.5Hz, Ar-H), 7.46 (m, 2H, Ar-H), 7.72 (brs, 1H, NH) ¹³C-NMR (125 MHz,CDCl₃) δ(ppm): 153.4 (3-carbamate)

EXAMPLE 74

Synthesis of11-{2-[N-methyl-N-(3-pyridylmethyl)amino]ethyl}amino-11-deoxy-3-O-(3-methylphenylamino)carbonyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Carrying out the same reaction as in Example 70(3) using 0.50 g (0.62mnmole) of the compound obtained in Example 70(2) and 0.33 g (3.10mmoles) of m-toluidine, there was obtained 0.18 g (yield: 32%) of thetitle compound.

Mass (IonSpray) m/z: 896.4 [M+H]⁺; ¹H-NMR (500 MHz, CDCl₃) δ(ppm): 0.74(t, 3H, J=7.3 Hz, H-15), 2.16 (s, 6H, 3′-N(CH₃)₂), 2.20 (s, 3H, NCH₃),2.33 (s, 3H, ArCH₃), 3.07 (s, 3H, 6-OCH₃), 4.96 (d, 1H, J=11.3 Hz, H-3),5.23 (dd, 1H, J=11.1, 2.1 Hz, H-13), 7.46 (brs, 1H, NH) ¹³C-NMR (125MHz, CDCl₃) δ(ppm): 21.5 (ArCH₃), 153.3 (3-carbamate)

EXAMPLE 75

Synthesis of11-{2-[N-methyl-N-(3-pyridylmethyl)amino]ethyl}amino-11-deoxy-3-O-(8-quinolineamino)carbonyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Carrying out the same reaction as in Example 70(3) using 0.50 g (0.62mmole) of the compound obtained in Example 70(2) and 0.45 g (3.1 mmoles)of 8-aminoquinoline, there was obtained 0.08 g (yield: 14%) of the titlecompound. Mass (IonSpray) m/z: 933 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃)δ(ppm): 0.76 (t, 3H, J=7.3 Hz, H-15), 1.92 (s, 6H, 3′-N(CH₃)₂), 2.21 (s,3H, NCH₃), 3.11 (s, 3H, 6-OCH₃), 5.08 (d, 1H, J=11.3 Hz, H-3), 5.26 (dd,1H, J=11.0, 2.3 Hz, H-13), 7.45-7.59 (m, 3H, quinolyl-H), 8.18 (dd, 1H,J=8.3, 1.6 Hz, quinolyl-H), 8.84 (dd, 1H, J=4.1, 1.6 Hz, quinolyl-H),9.32 (s, 1H, quinolyl-H)

EXAMPLE 76

Synthesis of11-{2-[N-methyl-N-(3-pyridylmethyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridylmethoxy)carbonyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Carrying out the same reaction as in Example 70(3) using 0.50 g (0.62nmmole) of the compound obtained in Example 70(2) and 0.34 g (3.10mmoles) of 2-pyridinemethanol, there was obtained 0.08 g (yield: 14%) ofthe title compound.

¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.74 (t, 3H, J=7.3 Hz, H-15), 2.19 (s,3H, NCH₃), 2.23 (s, 6H, 3′N(CH₃)₂), 3.04 (s, 3H, 6-OCH₃), 4.84 (d, 1H,J=11.1 Hz, H-3), 5.20 (d, 1H, J=13.2 Hz, OCH₂Py), 5.22 (dd, 1H, J=10.8,2.1 Hz, H-13), 5.38 (d, 1H, J=13.2 Hz, OCH₂Py)

EXAMPLE 77

Synthesis of11-{2-[N-methyl-N-(3-pyridylmethyl)amino]ethyl}amino-11-deoxy-3-O-(4-methoxyphenoxy)carbonyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Carrying out the same reaction as in Example 70(3) using 0.50 g (0.62mmole) of the compound obtained in Example 70(2) and 0.39 g (3.10mmoles) of p-methoxyphenol, there was obtained 0.15 g (yield: 26%) ofthe title compound.

Mass (SIMS) m/z: 913 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.75 (t,3H, J=7.3 Hz, H-15), 2.19 (s, 3H, NCH₃), 2.26 (s, 6H, 3′-N(CR₃)₂), 3.03(s, 3H, 6-OCH₃), 3.80 (s, 3H, ArOCH₃), 4.87 (d, 1H, J=11.2 Hz, H-3),5.22 (dd, 1H, J=11.0, 2.1 Hz, H-13)

EXAMPLE 78

Synthesis of11-{2-[N-methyl-N-(3-pyridylmethyl)amino]ethyl}amino-11-deoxy-3-O-(o-nitrophenyl)-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

(1) To a solution of 5.0 g (8.5 imoles) of5-O-desosaminyl-6-O-methylerythronolide A in 30 ml of tetrahydrofuranwas added 3.0 g (21 mmoles) of 2-fluoronitrobenzene. 0.30 g (13 mmoles)of sodium hydride was added to the mixture under ice-cooling, followedby stirring for 0.5 hour. The temperature was raised to roomtemperature, followed by stirring overnight. After the reaction, thereaction solution was cooled on ice, diluted with ethyl acetate andseparated with water. The organic layer was washed with a saturatedaqueous sodium chloride solution and dried over anhydrous magnesiumsulfate. After evaporation of the solvent under reduced pressure, theresidue was purified by silica gel column chromatography(chloroform:methanol=98:2) to give 1.6 g (yield: 27%) of3-O-(2-nitrophenyl)-5-O-desosaminyl-6-O-methylerythronolide A.

(2) 1.6 g (2.3 mmoles) of the compound obtained in the above (1) wasdissolved in 20 ml of acetone, and 0.25 ml (2.7 mmoles) of aceticanhydride was added thereto at room temperature, followed by stirringovernight. After evaporation of the solvent under reduced pressure, theresidue was diluted with ethyl acetate, and successively washed with asaturated aqueous sodium bicarbonate solution and a saturated aqueoussodium chloride solution. The organic layer was dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reduced pressureto give 1.7 g of the 2′-O-acetyl compound.

(3) To a solution of 1.7 g (2.3 mmoles) of the compound obtained in theabove (2) in 20 ml of methylene chloride was added 1.8 ml (23 mmoles) ofpyridine. 0.67 g (2.3 mmoles) of triphosgene was added thereto underice-cooling, followed by stirring for 2 hours. To the reaction solutionwas added water to decompose excess triphosgene, and the mixture wasdiluted with chloroform and successively washed with water and asaturated aqueous sodium chloride solution, and dried over anhydrousmagnesium sulfate. After evaporation of the solvent under reducedpressure, the resulting residue was dissolved in 15 ml ofN,N-dimethylformamide, and 0.39 g (3.4 mmoles) of1,1,3,3-tetramethylguanidine was added thereto, followed by stirring at100° C. for 3 hours. After allowing to stand for cooling, the mixturewas diluted with ethyl acetate and separated with water. The organiclayer was successively washed with water and a saturated aqueous sodiumchloride solution, and dried over anhydrous magnesium sulfate.Evaporation of the solvent under reduced pressure gave 1.6 g of10,11-anhydro-3-O-(o-nitrophenyl)-5-O-desosaminyl-6-O-methylerythronolideA.

(4) To a solution of 1.6 g (2.2 mmoles) of the compound obtained in theabove (3) in 20 ml of 1,2-dichloroethane were added 4.1 g (26 mmoles) of1,1′-carbonyldiimidazole and 1.6 g (12 mmoles) of4-dimethylaminopyridine, followed by heating under reflux for an hour.After allowing to stand for cooling, the reaction solution was dilutedwith chloroform, and separated with a saturated aqueous ammoniumchloride solution. The organic layer was successively washed with waterand a saturated aqueous sodium chloride solution, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give 1.1 g (yield: 64%) of the 12-O-imidazolylcarbonylcompound.

(5) To a solution of 0.5 g (0.63 mmole) of the compound obtained in theabove (4) in 5 ml of acetonitrile was added 1.0 g (6.3 mmoles) ofN-methyl-N-(3-pyridylmethyl)ethylenediamine, followed by stirring atroom temperature overnight. The reaction solution was diluted withchloroform, successively washed with a saturated aqueous ammoniumchloride solution and a saturated aqueous sodium chloride solution, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the resulting residue was dissolved in 20 ml ofmethanol, and heated under reflux for 2 hours. After allowing to standfor cooling, the solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography(chloroform:methanol:aqueous ammonia=30:1:0.1) to give 0.31 g (yield:56%) of the title compound.

Mass (SIMS) m/z: 884 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.74 (dd,3H, J=7.6, 6.0 Hz, H-15), 2.22 (s, 9H, NCH₃ and 3′-N(CH₃)₂), 3.08 (s,3H, 6-OCH₃), 4.60 (d, 1H, J=10.8 Hz, H-3), 5.21 (dd, 1H, J=11.0, 2.3 Hz,H-13), 7.03 (m, 1H, Ar-H), 7.28 (m, 1H, Ar-H), 7.55 (m, 1H, Ar-H), 7.75(m, 1H, Ar-H)

EXAMPLE 79

Synthesis of11-[2-(1-piperazinyl)ethyl]amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

(1) Carrying out the same reaction as in Example 78(3) using 53.56 g(0.085 mole) of 2′-O-acetyl-5-O-desosaminyl-6-O-methylerythronolide A,there was obtained 50.27 g (yield: 97%) of10,11-anhydro-2′-O-acetyl-5-O-desosaminyl-6-O-methylerythronolide A.

(2) Carrying out the same esterification at the 3-position as in Example1(4) using 50.27 g (0.082 mole) of the compound obtained in the above(1) and 42.65 g (0.25 mole) of 2-pyridylacetic acid hydrochloride, therewas obtained 41.95 g (yield: 70%) of10,11-anhydro-2′-O-acetyl-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA.

(3) To a solution of 31.01 g (0.042 mole) of the compound obtained inthe above (2) in 300 ml of a mixture of N,N-dimethylformamide andtetrahydrofuran (3:2) was added 20.58 g (0.126 mole) ofN,N′-carbonyldiimidazole at room temperature, then 3.38 g (0.084 mole)of 60% sodium hydride under ice-cooling, followed by stirring underice-cooling for 40 minutes. To the reaction solution was added water,followed by extraction with ethyl acetate. The ethyl acetate layer waswashed with water and a saturated aqueous sodium chloride solution, anddried over anhydrous magnesium sulfate. Evaporation of the solvent gave32.71 g (yield; 93%) of10,11-anhydro-2′-O-acetyl-12-O-imidazolylcarbonyl-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA.

(4) To a solution of 1.00 g (1.21 mmoles) of the compound obtained inthe above (3) in 10 ml of acetonitrile was added 1.56 g ofN-(2-aminoethyl)piperazine at room temperature, followed by stirring fora day. To the reaction solution was added an aqueous ammonium chloridesolution, followed by extraction with ethyl acetate. The ethyl acetatelayer was washed with water and a saturated aqueous sodium chloridesolution, and dried over anhydrous magnesium sulfate, and the solventwas evaporated. The residue was dissolved in 20 ml of methanol, andstirred at room temperature for 3 days, and the solvent was evaporated.The residue was purified by silica gel column chromatography (eluant;chloroform:methanol:aqueous ammonia=19:1:0.1˜9:1:0.1) to give 0.47 g(yield: 46%) of the title compound.

MS (IonSpray); m/z 884 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 2.29 (6H,s, N(CH₃ )₂), 3.03 (3H, s, 6-OCH₃ ), 5.06 (1H, d, J=11.3 Hz, 3-H), 5.31(1H, dd, J=11.0, 2.5 Hz, 13-H), 7.18-7.24 (1H, m, Py), 7.33-7.39 (1H, m,Py), 7.64-7.73 (1H, m, Py), 8.49-8.56 (1H, m, Py). ¹³C-NMR (75 MHz,CDCl₃) δ(ppm): 40.4 (Q, N(CH₃)₂), 50.2 (Q, 6-OCH₃), 216.2 (S, C1).

EXAMPLE 80

Synthesis of11-{2-[N-methyl-N-(3-pyridylmethyl)amino]propyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

(1) Carrying out the same reaction as in Example 79(4) using 3.0 g (3.41mmoles) of the compound obtained in Example 79(3) and 2.9 ml (34.1mmoles) of 1,2-diaminopropane, there was obtained 1.1 g of11-(2-aminopropyl)amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate.

(2) Carrying out the same reaction as in Example 3(1) using 1.1 g (1.17mmoles) of the compound obtained in the above (1), and then carrying outdeacetylation at the 2′-position by heating under reflux in methanol,there was obtained 1.0 g of the title compound.

MS (SIMS); m/z 896 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 2.16 (3H, s,NCH₃), 2.29 (6H, s, N(CH₃ )₂), 3.03 (3H, s, 6-OCH₃ )

EXAMPLE 81

Synthesis of11-{2-[N-methyl-N-(3-pyridylmethyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-cinnamylerythronolideA 11,12-cyclic carbamate

(1) 22.9 g (0.022 mole) of 2′,4″-O-bis-(trimethylsilyl)erythromycin A9-{O-[1-(1-methylethoxy)-cyclohexyl]oxime} described in U.S. Pat. No.4,990,602 was dissolved in 230 ml of dimethyl sulfoxide-tetrahydrofuran(1:1), and then 13.1 g of cinnamyl bromide and 2.59 g of 96% potassiumhydroxide were added thereto under ice-cooling, followed by stirringunder ice-cooling for 1.5 hours. After the reaction, 5 ml of 50% aqueousdimethylamine solution was added to the mixture, followed by stirring atroom temperature for 30 minutes. Water was added to the mixture,followed by extraction with hexane. The hexane layer was washed with asaturated aqueous sodium chloride solution and dried over anhydrousmagnesium sulfate, and the hexane was evaporated. To a solution of theresulting residue in 150 ml of ethanol were added 2.83 ml of 90% formicacid and 150 ml of water at room temperature, the mixture was heatedunder reflux for an hour, and then 16.1 g of sodium hydrogen sulfite wasadded thereto, followed by heating under reflux for further 2 hours. Thereaction solution was concentrated, and adjusted to pH 11 with 2Naqueous sodium hydroxide solution under ice-cooling. Water was added tothe mixture, followed by extraction with ethyl acetate. The ethylacetate layer was washed with a saturated aqueous sodium chloridesolution and dried over anhydrous magnesium sulfate, and the ethylacetate was evaporated. The resulting residue was purified by silica gelcolumn chromatography (eluant; chloroform:methanol:aqueousammonia=94:6:0.6-9:1:0.1) to give 7.76 g of 6-O-cinnamylerythromycin A.

MS (FAB) m/z; 850 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 2.29 (6H, s,N(CH₃)2), 3.34 (3H, s, OCH₃), 4.00, 4.20 (each 1H, each dd, J=4.7, 10.9Hz, OCH₂ CH═CHPh), 6.32 (1H, ddd, J=4.7, 10.9, 15.7 Hz, OCH₂CH═CHPh),6.47 (1H, d, J=15.7 Hz, OCH₂CH═CHPh)

(2) To a solution of 7.00 g (8.23 mmoles) of the compound obtained inthe above (1) in 7 ml of ethanol was added 70 ml of 1N hydrochloricacid, followed by stirring at room temperature for 3.5 hours. Thereaction solution was extracted with chloroform, and the chloroformlayer was successively washed with dil. hydrochloric acid, an aqueoussodium hydroxide solution and a saturated aqueous sodium chloridesolution, and dried over anhydrous magnesium sulfate. After evaporationof the solvent, the resulting residue was dissolved in 30 ml of acetone,and 1.26 g of acetic anhydride was added thereto at room temperature,followed by stirring at room temperature for 1.5 hours. Afterevaporation of the acetone, the residue was extracted with ethylacetate, washed with a saturated aqueous sodium bicarbonate solution anda saturated aqueous sodium chloride solution, and dried over anhydrousmagnesium sulfate. After evaporation of the ethyl acetate, the residuewas purified by silica gel column chromatography (eluant;acetone:hexane:triethylamine=6:10:0.2) to give 4.2 g of2′-O-acetyl-5-O-desosaminyl-6-O-cinnamylerythronolide A.

(3) Carrying out the same reaction as in Example 2 using 0.49 g (0.7mmole) of the compound obtained in the above (2), and then crystallizingfrom dichloromethane-isopropyl ether, there was obtained 0.30 g of3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-0-cinnamylerythronolide A.

MS (FAB) m/z; 811 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 2.28 (6H, s,N(CH₃)₂), 5.12 (1H, d, 3-H) ¹³C-NMR (75 MHz, CDCl₃) δ(ppm): 40.2 (Q.N(CH₃)₂), 170.4 (S, 3-OCO-), 173.3 (C1), 219.5 (C9)

(4) Carrying out the same reactions as in Examples 78(2), 78(3), 79(3),1(1) and 3(1) successively, using 0.75 g of the compound obtained in theabove (3), there was obtained 0.5 g of the title compound.

MS (FAB) m/z; 984 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 2.01 (3H, s,NCH₃), 2.30 (6H, s, N(CH₃)₂).

EXAMPLE 82

Synthesis of11-{2-[1,2-bis(ethoxycarbonyl)vinylamino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

To a solution of 0.5 g (0.64 mmole) of the compound obtained in Example38(3) in 20 ml of methylene chloride was added 0.11 ml (0.71 mmole) ofdiethylacetylenedicarboxylate at room temperature, followed by reactionfor 5 hours. After evaporation of the solvent under reduced pressure,the resulting residue was purified by silica gel column chromatography(eluant; chloroform:methanol:aqueous ammonia=9:1:0.1) to give 366 mg ofthe title compound as a yellow foam.

MS (FAB) m/z; 947 [M+H]⁺.

EXAMPLE 83

Synthesis of11-{2-[N-(3-quinolylmethyl)amino]ethyl}amino-11-deoxy-3-O-(2-pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythronolideA 11,12-cyclic carbamate

Following the same procedure as in Example 50 using a solution of 1.0 g(1.28 mmoles) of the compound obtained in Example 38(3) in 20 ml ofmethylene chloride and 0.24 g (1.55 mmoles) of 3-quinolinecarboxaldehydein place of 2-hydroxy-4-methoxybenzaldehyde, there was obtained 0.35 g(yield: 32%) of the title compound.

MS (IonSpray) m/z; 918.5 [M+H]⁺;.

Experiment [In vitro Antibacterial Activity]

The in vitro antibacterial activity of the compound obtained in Example4 as an example of the compound of the present invention against variousexperimental bacteria was measured using sensitive disc media (producedby Eiken Chemical Co.) according to the MIC measuring method specifiedby the Japan Society of Chemotherapy. Clarithromycin was used as acomparative drug. The results are expressed as MIC value (MinimumInhibitory Concentration, μg/ml), and shown in Table 1. The compoundobtained in Example 4 shows to have a strong antibacterial activity notonly against erythromycin-sensitive bacteria but alsoerythromycin-resistant bacteria.

TABLE 1 In Vitro Antibacterial Activity: MIC (μg/ml) Compound ofComparative Microorganism/Compound Example 4 drug S. aureus 209P-JC 0.100.10 S. aureus Smith 0.20 0.20 S. aureus J-109 >100 >100 S. aureus B10.39 >100 S. pneumoniae IID 553 0.10 0.10 S. pneumoniae BM 210 0.39 1.56S. pneumoniae BM 205 0.39 >100

Industrial Applicability

The compounds of the present invention have an antibacterial activityagainst not only erythromycin-sensitive bacteria but alsoerythromycin-resistant bacteria. Therefore, the compounds of the presentinvention are useful as antibacterial agents for the treatment ofbacterially infectious diseases in human beings and animals (includingfarm animals).

What is claimed is:
 1. An erythrornycin A derivative represented byFormula (I):

wherein n is an integer of from 1 to 4, R¹ is a group represented by theformula:

wherein p is 0 or 1, Z is a nitrogen atom or CH; R⁷, R⁸ and R⁹ are eacha hydrogen atom, a halogen atom, an alkyl group having 1 to 5 carbonatoms, a nitro group, an amino group, an acetylamino group, an aminogroup substituted by 1 or 2 alkyl groups having 1 to 3 carbon atoms, ahydroxyl group, a cyano group, an alkyl group having 1 to 3 carbon atomssubstituted by 1 to 3 halogen atoms, an alkoxy group having 1 to 5carbon atoms or a phenyl group, or R⁷ and R⁸ are attached to the carbonatoms which are attached side by side, and together form amethylenedioxy group, or R⁷ and R⁸ are attached to the carbon atomswhich are attached side by side, and together with the carbon atoms towhich they attached form a benzene ring, R¹⁰ and R¹¹ are each a hydrogenatom, or R¹⁰ and R¹¹ together form an oxo group, a group represented bythe formula:

wherein R¹⁰ and R¹¹ are as defined above, M is an oxygen atom, a sulfuratom, —NCH₃ or —NH, or R¹² and R¹³ are each a hydrogen atom, or R¹² andR¹³ together with the carbon atoms to which they are attached form abenzene ring, (c) a pyridylacetyl group, (d) a cycloalkylmethyl grouphaving 4 to 8 carbon atoms or (e) a 1,2-bis(ethoxy-carbonyl)vinyl group,R² is the same group as defined for R¹, a hydrogen atom, an alkyl grouphaving 1 to 5 carbon atoms, an alkanoyl group having 2 to 6 carbon atomsor an alkoxycarbonyl group having 2 to 6 carbon atoms, R¹ and R²together form a group of the formula: ═CH—R¹⁴ wherein R¹⁴ is a phenylgroup, a phenyl group substituted by nitro group(s), cyano group(s) oralkyl group(s) having 1 to 3 carbon atoms substituted by 1 to 3 halogenatoms, or an imidazolyl group, or R¹ and R² together with the nitrogenatom to which they are attached form a group represented by the formula:

wherein W is CH, a carbon atom or a nitrogen atom, Y is a group of—C(═O) or —(CH₂)_(m)— wherein m is 1 or 2, R¹⁵ and R¹⁶ are each ahydrogen atom or when W is a 5 carbon atom, R¹⁵ and R¹⁶ together withthe carbon atoms to which they are attached form a benzene ring or anaphthalene ring, R³ is a hydrogen atom, an alkyl group having 1 to 5carbon atoms or a cinnamyl group, R⁴ is a hydrogen atom, an acetylgroup, an ethylsuccinyl group or a nicotinoyl group, A is a grouprepresented by the formula: —OC(═O)—R¹⁷, —OC(═O)—CH₂—R¹⁷,—OC(═O)—NH—R¹⁷, —O—R¹⁷ or —OC(═O)—O—R¹⁷ wherein R¹⁷ is a phenyl group, apyridyl group, a quinolyl group, or those groups which are eachsubstituted by 1 to 3 members selected from the group consisting of analkyl group having 1 to 5 carbon atoms, a nitro group, an alkoxy grouphaving 1 to 5 carbon atoms and a halogen atom, and R⁵ and R⁶ are each ahydrogen atom or an alkyl group having 1 to 5 carbon atoms or apharmaceutically acceptable salt thereof.
 2. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and aneffective amount of the erythromycin A derivative or a pharmaceuticallyacceptable salt thereof according to claim
 1. 3. An antibacterialpreparation comprising a pharmaceutically acceptable carrier and aneffective amount of the erythromycin A derivative or thepharmaceutically acceptable salt thereof according to claim 1 as aneffective component.
 4. A method for the treatment of a bacteriallyinfectious disease which comprises administering a pharmaceuticallyeffective amount of the erythromycin A derivative or a pharmaceuticallyacceptable salt thereof according to claim 1 to a patient.